@article {pmid40473085,
year = {2025},
author = {Caldero-Escudero, E and Romero-Sanz, S and Álvarez-Illera, P and De la Fuente, S and García-Casas, P and Fonteriz, RI and Montero, M and Álvarez, J and Santo-Domingo, J},
title = {Calreticulin (crt-1) silencing reduces Aß1-42-induced toxicity and restores muscle function in C. elegans.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {167946},
doi = {10.1016/j.bbadis.2025.167946},
pmid = {40473085},
issn = {1879-260X},
abstract = {Accumulation of aggregated β-amyloid peptide is a key histopathological feature of Alzheimer's Disease (AD). Experimental models of AD based on β-amyloid peptide display calcium (Ca[2+]) signaling alterations, and targeting key components of the cellular Ca[2+] signaling system has been postulated to modulate AD onset and progression. Here we have taken advantage of a C. elegans strain that over-expresses the most toxic human ß-amyloid peptide (Aß1-42) in body-wall muscle cells, to study the impact of calreticulin (crt-1) silencing on body-wall muscle performance. Crt-1 knockdown reduced the percentage of paralyzed worms in a dose-dependent manner and improved locomotion parameters in free-mobility assays in Aß1-42-overexpressing worms. At the cellular level, crt-1 silencing prevented Aß1-42-induced exacerbated mitochondrial respiration and mitochondrial ROS production without impacting mitochondrial sarcomere organization. Crt-1 knockdown reduced the number and size of Aß1-42 aggregates in body-wall muscle cells and prevented the formation of Aß1-42 oligomers. We propose that crt-1 depletion reduces the number of Aß1-42 aggregates, precluding Aß1-42-induced mitochondrial toxicity and improving muscle function. We identify C. elegans crt-1 as a gene involved in the toxicity associated with the expression of human Aß1-42, and thus a potential new target for treatment.},
}

@article {pmid40473076,
year = {2025},
author = {Fang, J and Shi, Y and Ba, L and Zhang, M and Li, M and Zheng, N and Qin, Y and Zhu, W},
title = {Gray Matter and White Matter Functional Connectivity Changes induced by rTMS concurrent with Cognitive training in Alzheimer's disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111418},
doi = {10.1016/j.brainresbull.2025.111418},
pmid = {40473076},
issn = {1873-2747},
abstract = {BACKGROUND AND PURPOSE: Primarily by targeting the gray matter (GM), repetitive transcranial magnetic stimulation (rTMS) has shown promise in improving cognitive function in individuals with Alzheimer's disease (AD). However, the impact of rTMS on white matter (WM) remains poorly understood. This study aimed to investigate the functional connectivity (FC) changes in both GM and WM induced by rTMS, and explore their relationship with the clinical manifestation of the disease.

METHODS: Sixteen patients with mild to moderate AD were enrolled and randomly assigned to either the real rTMS group (n = 8) or the sham treatment group (n = 8). Both groups received cognitive training in combination with rTMS. The real rTMS group received 10Hz stimulation targeting the left dorsolateral prefrontal cortex (DLPFC) followed by the left lateral temporal lobe (LTL), with each session lasting 20minutes per day for 4 weeks, while sham with the coil positioned at a 90° angle. Resting-state BOLD signals were averaged to generate mean time series for each of the 82 GM regions and 48 WM bundles, both before and after treatment for each subject. We analyzed the resting-state fMRI data by using a 2 × 2 factorial design with "time" as the within-subjects factor and "group" as the between-subjects factor.

RESULTS: In the analysis of 82 GM regions, when using left LTL as the seed, significant time main effect was observed in right ventral Posterior cingulate cortex (vPCC) (F=9.356, p=0.009, η[2]=0.401) and right inferior temporal gyrus (ITG) (F=11.784, p=0.004, η[2]=0.457). In the analysis of 48 WM bundles, when using left DLPFC as the seed, significant time × group interactions were found in right cingulum (hippocampus part, CGH) (F=12.123, p=0.004, η[2]=0.464). The FC between left DLPFC and right cerebral peduncle (CBRP) demonstrated significant time main effect (F=15.569, p=0.001, η[2]=0.527). Moreover, the FC between left DLPFC and right CGH was significantly correlated with MMSE scores changes (r =-0.610, p=0.027), reflecting cognitive improvements after treatment.

CONCLUSION: The current study suggested that rTMS, when combined with cognitive training, can concurrently modulate functional activities in both GM and WM in patients with mild to moderate AD, which are associated with cognitive improvements. Notably, the limbic system appears to play a pivotal role in facilitating this therapeutic process.},
}

@article {pmid40472637,
year = {2025},
author = {Doulberis, M and Tsilimpotis, D and Polyzos, SA and Vardaka, E and Salahi-Niri, A and Yadegar, A and Kountouras, J},
title = {Unraveling the pathogenetic overlap of Helicobacter pylori and metabolic syndrome-related Porphyromonas gingivalis: Gingipains at the crossroads and as common denominator.},
journal = {Microbiological research},
volume = {299},
number = {},
pages = {128255},
doi = {10.1016/j.micres.2025.128255},
pmid = {40472637},
issn = {1618-0623},
abstract = {Chronic bacterial infections exert profound systemic effects beyond their primary infection sites, influencing a range of inflammatory, metabolic, and neurodegenerative diseases. Helicobacter pylori (Hp) and Porphyromonas gingivalis (Pg) are two highly prevalent pathogens that, despite occupying distinct niches, share remarkable pathogenic similarities. Both bacteria, connected with metabolic syndrome, employ immune evasion strategies, induce chronic inflammation, and contribute to systemic diseases such as metabolic-associated steatotic liver disease, cardiovascular disease, and neurodegeneration, such as Alzheimer's disease. A key unifying factor in their pathogenicity is the role of gingipains-cysteine proteases produced by Pg-which facilitate bacterial invasion, immune modulation, and tissue destruction. Emerging evidence suggests that Hp possesses analogous proteolytic enzymes, further supporting their potential synergistic impact on host health. Moreover, both pathogens have been implicated in metabolic syndrome-related blood-brain barrier disruption, chronic (smoldering) systemic inflammation, and lipid metabolism dysregulation, contributing to progressive neurodegenerative and cardiovascular disorders. The role of galectins, particularly galectin-3, in modulating microglial activation and inflammatory pathways further highlights their involvement in neuroinflammatory diseases. Targeting gingipains presents a promising therapeutic avenue, with bismuth compounds and novel inhibitors showing potential in disrupting these proteases and mitigating their systemic effects. Understanding the interactions between Hp and metabolic syndrome-related Pg is crucial for developing comprehensive treatment strategies, integrating gastroenterology, periodontology, and neurology. Addressing these infections at both local and systemic levels may improve long-term health outcomes and reduce the burden of chronic inflammatory diseases linked to microbial persistence.},
}

@article {pmid40470974,
year = {2025},
author = {Li, Z and Ma, JL and Yang, J and Sun, T and Xiao, B and Han, M and Ma, H and Wang, ZZ and Su, Y and Song, J and Li, X and Wang, P and Zhang, Z},
title = {Discovery of Atractylenolide Derivatives as Novel LSD1 Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c02433},
pmid = {40470974},
issn = {1520-5118},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cognitive decline and memory impairment. Current treatments offer only symptomatic relief, underscoring the urgent need for novel therapeutic strategies. Lysine-specific demethylase 1 (LSD1) plays a crucial role in gene transcription regulation and has emerged as a potential therapeutic target for AD. Building on our previous research on Atractylodes macrocephala, a traditional medicinal plant, this study reported chemical modifications on the sesquiterpene scaffold in Atractylodes. The compounds were evaluated for their LSD1 inhibitory activity and anti-AD properties in both in vitro and in vivo studies. Notably, compound A1 exhibited potent LSD1 inhibition, with an IC50 value of 0.8 μM. In vitro assays demonstrated that A1 significantly inhibits Aβ aggregation and enhances Aβ-induced neuronal cell viability. Molecular dynamics results revealed stable binding interactions of A1 with LSD1 and Aβ. Furthermore, in vivo studies using APP/PS1 transgenic mice showed that A1 treatment improved cognitive function and learning abilities, reduced neuroinflammation by inhibiting the activation of microglia and astrocytes, and decreased Aβ deposition in the hippocampus of AD mice. These findings suggest that compound A1 is a promising candidate for the development of an effective therapy for AD, underscoring the therapeutic potential of novel LSD1 inhibitors.},
}

@article {pmid40470403,
year = {2025},
author = {Abbas Raja, A and Amjad, A and Choudhary, A and Atta, A and Atta, M and Hussain, S and Khan, M},
title = {Comparative Effectiveness of Rivastigmine and Donepezil in Patients With Alzheimer's Disease: A Retrospective Cohort Study.},
journal = {Cureus},
volume = {17},
number = {5},
pages = {e83498},
pmid = {40470403},
issn = {2168-8184},
abstract = {This is a retrospective cohort study comparing the effectiveness of rivastigmine and donepezil in Alzheimer's disease (AD) patients. Of the 250 subjects, 127 (50.8%) were men, while 123 (49.2%) were women. Baseline cognitive function was assessed using the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). The results showed that 83 (33.2%) patients improved, 84 (33.6%) remained stable, and 83 (33.2%) experienced cognitive decline. The difference between the two groups was not significant with respect to cognitive outcomes (Chi-square = 0.08, df = 2, N = 250, p = 0.96). However, rivastigmine was associated with a higher rate of side effects (65, or 52%), which could hinder adherence. Both groups had an average of 1.48 hospitalization episodes per patient. Biomarker analysis suggested that 144 (57.6%) of patients tested positive for amyloid on positron emission tomography (PET) scans. Cerebrospinal fluid (CSF) analysis data, illustrated through mean values, showed amyloid beta at 546.38 pg/mL and tau at 219.85 pg/mL - both linked to cognitive decline. Higher levels of tau were significantly correlated with greater cognitive decline. Statistically, there were significant differences between the treatment groups in terms of MMSE scores and CSF biomarkers (p < 0.05). Although there was no statistically significant difference in cognitive outcomes between the drugs, subgroup analysis revealed significant differences in baseline MMSE scores and CSF biomarker levels (p < 0.05), suggesting heterogeneity in disease severity. Therefore, personalized strategies for managing patients with AD should be constructed based on the drug's side effect profile, comorbidities, and biomarker status. Future studies should focus on biomarker-directed and combination therapies to improve treatment efficacy.},
}

@article {pmid40469853,
year = {2025},
author = {Buracchio, T and Campbell, M and Krudys, K},
title = {Assessing clinical meaningfulness in clinical trials for Alzheimer's disease: A U.S. regulatory perspective.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70113},
pmid = {40469853},
issn = {2352-8737},
abstract = {UNLABELLED: In the context of recent approvals of amyloid-directed monoclonal antibodies for the treatment of Alzheimer's disease (AD) by the United States (U.S.) Food and Drug administration (FDA), there has been much public discussion regarding the meaningfulness of the treatment effects demonstrated with these drugs in clinical trials. There are a variety of regulatory approaches to evaluate how results on a clinical endpoint reflect a meaningful effect of an intervention, including qualitative and quantitative methodologies. This article will discuss regulatory considerations for clinical benefit across the stages of AD, approaches to the assessment of clinical meaningfulness in clinical trials, and FDA's assessment of clinical benefit in the recent traditional approvals of amyloid-directed monoclonal antibodies for the treatment of AD.

HIGHLIGHTS: Assessment of clinical benefit will depend on the stage of Alzheimer's disease (AD) being studied, the clinical symptoms or findings that occur at that stage of disease, and the mechanism of the drug and its anticipated effects.It is critical to obtain input from patients and caregivers with lived experience to understand their perspectives on clinical benefit.The Food and Drug Administration (FDA) encourages the use of clinically meaningful within-patient change, which captures the assessment of improvement or decline based on the perspective of the individual patient, to assess meaningful score differences.},
}

@article {pmid40469843,
year = {2025},
author = {Kang, J and Liu, M and Yang, Q and Dang, X and Li, Q and Wang, T and Qiu, B and Zhang, Y and Guo, X and Li, X and Liu, Y},
title = {Exercise training exerts beneficial effects on Alzheimer's disease through multiple signaling pathways.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1558078},
pmid = {40469843},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive dysfunction that affects millions of people worldwide, placing a massive burden on families and economies. Exercise training can effectively reduce the prevalence of AD and alleviate its symptoms through the modulation of multiple signaling pathways involved in the pathophysiological process of AD, including the PI3K/Akt, Wnt/β-catenin, AMPK-related, MAPK, NF-κB, PINK1-PARKIN, JAK/STAT, and TREM2 signaling pathways. Different signaling pathways also crosstalk with each other through different targets to inhibit the formation of Amyloid β (Aβ) plaques, reduce the level of hyperphosphorylated tau protein, reduce apoptosis, relieve neuroinflammation, reduce autophagy dysfunction, and ultimately improve cognitive impairment in AD patients. This review summarizes the pathophysiological processes of AD affected by exercise training through different signaling pathways. We further provide a reference for the future development of new effective AD prevention and treatment targets to develop promising personalized, combined intervention strategies.},
}

@article {pmid40469696,
year = {2025},
author = {Wang, C and Song, X and Zhang, X and Li, P and Wei, W and Sun, S and Chen, Y},
title = {Multifunctional natural chlorogenic acid based nanocarrier for Alzheimer's disease treatment.},
journal = {Materials today. Bio},
volume = {32},
number = {},
pages = {101841},
pmid = {40469696},
issn = {2590-0064},
abstract = {Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of chlorogenic acid (CHA), a multifunctional natural active compound, in AD therapy by developing a trifunctional nanocarrier (MC-H/R/si). CHA was effectively conjugated with iron-based metal-organic frameworks (MIL/Fe-100) through chelation interaction. The resulting nanocomplex (MC) not only enhances the bioavailability of CHA but also facilitates a synergistic antioxidant effect between CHA and MIL/Fe-100. Importantly, CHA can chelate Zn[2+] from β-amyloid/Zn[2+] (Aβ/Zn[2+]) polymers, inhibiting Aβ aggregation. Furthermore, small interfering RNA targeting BACE1 was covalently linked to MC to downregulate BACE1 expression. Both in vitro and in vivo experiments revealed that MC-H/R/si effectively scavenges ROS, reduces inflammation and Aβ plaque, and improves the learning and cognitive abilities of APP/PS1 mice. These findings confirm that the trifunctional nanocarrier MC-H/R/si has great potential for AD treatment.},
}

@article {pmid40468463,
year = {2025},
author = {Lei, L and Cheng, Y and Yin, A and Han, JM and Wu, G and Yang, F and Wang, Q and Wang, JZ and Liu, R and Li, HL and Wang, X},
title = {Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {29},
pmid = {40468463},
issn = {2047-9158},
support = {82330041//National Natural Science Foundation of China/ ; 82071440//National Natural Science Foundation of China/ ; },
mesh = {Animals ; YAP-Signaling Proteins ; Mice, Inbred C57BL ; *Alzheimer Disease/metabolism/pathology/genetics ; Mice ; *Aging/metabolism/pathology ; Signal Transduction/physiology ; *Proto-Oncogene Proteins c-akt/metabolism ; Hippocampus/metabolism/pathology ; Male ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Adaptor Proteins, Signal Transducing/metabolism ; Up-Regulation/physiology ; Rats ; Humans ; Cell Cycle Proteins/metabolism ; Neurons/metabolism ; },
abstract = {BACKGROUND: Aging is the greatest risk factor for late-onset Alzheimer's disease (LOAD), which accounts for > 95% of all Alzheimer's disease (AD) cases. Yes-associated protein 1 (YAP1), an aging-dependent protein, is a key element in the classical Hippo-YAP1 pathway mediated by a kinase cascade. Research showed that YAP1 was markedly reduced in the brains of individuals with AD. However, the mechanisms underlying the susceptibility of the Hippo-YAP1 signaling pathway in the context of LOAD remain unclear.

METHODS: AAV9-YAP1-RNAi was injected into the hippocampi of C57BL/6J mice to establish a YAP1 knockdown model. Overexpression of full-length YAP1 was achieved by injecting AAV9-YAP1 into the hippocampi of SAMP8 mice. To establish the model of knockdown of nuclear receptor subfamily 4 group A member 1 (Nr4a1), AAV9-Nr4a1-RNAi was injected into the hippocampi of SAMP8 mice. In the C57BL/6J mice with YAP1 knockdown, Nr4a1 expression was either knocked down or inhibited with DIM-C to examine the impact of Nr4a1 on tau phosphorylation and cognitive deficits. Primary hippocampal neurons from Sprague-Dawley (SD) rats were infected with lentivirus (LV)-YAP1 to create a YAP1 overexpression model, and Aβ treatment was used to induce neuronal senescence. Protein levels were assessed using immunofluorescence, Western blotting, and ELISA. Animal behavior was evaluated using the Morris water maze test, novel object recognition test, and open field test.

RESULTS: YAP1 was reduced in the hippocampus of both aged C57BL/6J mice and SAMP8 AD model mice through Hippo pathway activation, as well as in Aβ-induced senescent neurons. Overexpression of YAP1 in primary neurons significantly mitigated the Aβ-induced neuronal senescence by downregulating several senescence-related genes, including p16 and p53. The levels of phosphorylated AKT/GSK-3β in neurons were increased with overexpression of YAP1 both in vivo and in vitro. Knockdown of YAP1 induced AD-like symptoms and exacerbated cognitive decline in 2-month-old C57BL/6J mice. Injection of AAV9-YAP1 in the brains of SAMP8 mice partially alleviated neuronal senescence and enhanced cognitive function. Notably, genetic knockdown and chemical inhibition of Nr4a1 significantly ameliorated cognitive deficits as well as AD-like pathology in these subjects.

CONCLUSIONS: These findings reveal an etiopathogenic relationship between aging and AD, which is associated with the YAP1-Nr4a1-AKT/GSK-3β signaling pathway. Our findings provide insight into the therapeutic strategies aimed at delaying brain aging and combating neurodegenerative diseases such as AD.},
}

Animals
YAP-Signaling Proteins
Mice, Inbred C57BL
*Alzheimer Disease/metabolism/pathology/genetics
Mice
*Aging/metabolism/pathology
Signal Transduction/physiology
*Proto-Oncogene Proteins c-akt/metabolism
Hippocampus/metabolism/pathology
Male
*Glycogen Synthase Kinase 3 beta/metabolism
*Adaptor Proteins, Signal Transducing/metabolism
Up-Regulation/physiology
Rats
Humans
Cell Cycle Proteins/metabolism
Neurons/metabolism

@article {pmid40468377,
year = {2025},
author = {Wang, Z and Zhang, L and Qin, C},
title = {Alzheimer's disease pathogenesis: standing at the crossroad of lipid metabolism and immune response.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {67},
pmid = {40468377},
issn = {1750-1326},
support = {2021-I2M-1-034//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 2023-PT180-01//Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences/ ; },
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism/pathology ; *Lipid Metabolism/physiology/immunology ; Animals ; Brain/metabolism/immunology/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by macroscopic features such as cortical atrophy, narrowing of the gyri, widening of the sulci, and enlargement of the ventricles. At the cellular level, the pathological characteristics include the extracellular aggregation of β-amyloid (Aβ) forming senile plaques, and the intracellular accumulation of hyperphosphorylated tau proteins forming neurofibrillary tangles. AD leads to the progressive decline of cognitive, behavioral, and social abilities, with no effective treatment available currently. The pathophysiology of AD is complex, involving mechanisms such as immune dysregulation and lipid metabolism alterations. Immune cells, such as microglia, can identify and clear pathological aggregates like Aβ early in the disease. However, prolonged or excessive activation of immune cells may trigger chronic neuroinflammation, thereby accelerating neuronal damage and the progression of AD. Lipid metabolism plays a critical role in maintaining cell membrane structure and function, regulating the production and clearance of Aβ, and supplying energy to the brain. Disruptions in these processes are closely linked to the pathological progression of AD. The interaction between lipid metabolism and the immune system further exacerbates the disease progression of AD. In this review, we discuss the lipid metabolism and immune response in AD, summarize their intricate interactions, and highlight the complexity of the multifactorial pathogenic cascade, offering insights into new interventions targeting the immune-metabolic axis in AD.},
}

Humans
*Alzheimer Disease/immunology/metabolism/pathology
*Lipid Metabolism/physiology/immunology
Animals
Brain/metabolism/immunology/pathology
Amyloid beta-Peptides/metabolism

@article {pmid40467939,
year = {2025},
author = {Verma, H and Dhureja, M and Yadav, A and Yadav, B and Rao, R and Dhiman, M and Kumar, P and Mantha, AK},
title = {An In Vivo C57BL/6 Mouse Study Demonstrating Fine-Tuning of Serum and Brain-Derived Exosomes Reveal Therapeutic Potential of Phytochemical Ferulic Acid Against Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40467939},
issn = {1559-1182},
support = {CRG/2021/002524//SERB/ ; CRG/2021/002524//SERB/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by memory loss, synaptic impairment, and biochemical changes. The study aimed to investigate the neuroprotective role of ferulic acid (FA) in an AD mouse C57BL/6 model induced by the Aβ(25-35) peptide. Cognitive deficits, which include memory and spatial learning deficits caused by Aβ, were evaluated using a set of behavioural tests. Transmission electron microscopy (TEM), dynamic light scattering (DLS), and Western blot analysis were used to characterize the exosomes from the brain and the serum. The activity of acetylcholinesterase (AChE) in exosomes was also evaluated, and the proteomic analysis of the serum-derived exosomes was conducted through LC-MS Triple ToF and bioinformatics to identify the altered pathways associated with identified proteins. The results obtained showed that there were significant alterations in the exosomal proteome profile after Aβ treatment. The levels of some of the proteins that are involved in energy metabolism, amyloid clearance, cytoskeleton, oxidative stress, and neuroinflammation were particularly affected. Treatment with the phytochemical FA modulated the exosomal proteome profile alterations and the activity of AChE in exosomes, which are some of the hallmarks of cholinergic dysfunction in the case of AD. However, the analysis of the proteome of the AD condition revealed that there were distinct alterations in the content of serum-derived exosomes, which could be used as candidates for non-invasive biomarkers of AD progression. This work also highlights the possibility of using the phytochemical FA to prevent and treat the neurotoxicity and neurodegenerative cascade induced by Aβ and to correct the protein content of exosomes in AD.},
}

@article {pmid40467562,
year = {2025},
author = {Wang, Y and Song, P and Zhou, H and Wang, P and Li, Y and Shao, Z and Wang, L and You, Y and Lei, Z and Yu, J and Li, C},
title = {An AI-assisted fluorescence microscopic system for screening mitophagy inducers by simultaneous analysis of mitophagic intermediates.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {5179},
pmid = {40467562},
issn = {2041-1723},
support = {92159304, 82394433, 82227806,82025019//National Natural Science Foundation of China (National Science Foundation of China)/ ; 22174023, 22378072//National Natural Science Foundation of China (National Science Foundation of China)/ ; 22ZR1414700//Natural Science Foundation of Shanghai (Natural Science Foundation of Shanghai Municipality)/ ; },
mesh = {*Mitophagy/drug effects ; Humans ; *Mitochondria/metabolism/drug effects ; Microscopy, Fluorescence/methods ; Animals ; Alzheimer Disease/metabolism/pathology/drug therapy ; Autophagosomes/metabolism/drug effects ; Mice ; *Artificial Intelligence ; Amyloid beta-Peptides/metabolism ; Lysosomes/metabolism/drug effects ; HeLa Cells ; },
abstract = {Mitophagy, the selective autophagic elimination of mitochondria, is essential for maintaining mitochondrial quality and cell homeostasis. Impairment of mitophagy flux, a process involving multiple sequential intermediates, is implicated in the onset of numerous neurodegenerative diseases. Screening mitophagy inducers, particularly understanding their impact on mitophagic intermediates, is crucial for neurodegenerative disease treatment. However, existing techniques do not allow simultaneous visualization of distinct mitophagic intermediates in live cells. Here, we introduce an artificial intelligence-assisted fluorescence microscopic system (AI-FM) that enables the uninterrupted recognition and quantification of key mitophagic intermediates by extracting mitochondrial pH and morphological features. Using AI-FM, we identify a potential mitophagy modulator, Y040-7904, which enhances mitophagy by promoting mitochondria transport to autophagosomes and the fusion of autophagosomes with autolysosomes. Y040-7904 also reduces amyloid-β pathologies in both in vitro and in vivo models of Alzheimer's disease. This work offers an approach for visualizing the entire mitophagy flux, advancing the understanding of mitophagy-related mechanisms and enabling the discovery of mitophagy inducers for neurodegenerative diseases.},
}

*Mitophagy/drug effects
Humans
*Mitochondria/metabolism/drug effects
Microscopy, Fluorescence/methods
Animals
Alzheimer Disease/metabolism/pathology/drug therapy
Autophagosomes/metabolism/drug effects
Mice
*Artificial Intelligence
Amyloid beta-Peptides/metabolism
Lysosomes/metabolism/drug effects
HeLa Cells

@article {pmid40467024,
year = {2025},
author = {Hu, X and Morihara, R and Fukui, Y and Bian, Y and Sun, H and Ota-Elliott, RS and Ishiura, H and Abe, K and Yamashita, T},
title = {Spearmint extract Neumentix downregulates amyloid-β accumulation by promoting phagocytosis in APP23 mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {149752},
doi = {10.1016/j.brainres.2025.149752},
pmid = {40467024},
issn = {1872-6240},
abstract = {In recent years, many researchers have focused on natural compounds that can effectively delay symptoms of Alzheimer's disease (AD). The spearmint extract Neumentix, which is rich in phenolic compounds, has been shown to reduce inflammatory responses and oxidative stress in mice. However, the effect of Neumentix on AD has not been thoroughly studied. In this study, APP23 transgenic female and male mice were administered Neumentix orally from 4 to 18 months of age at a dosage of 2.65 g/kg/day (containing 0.41 g/kg/day of rosmarinic acid). The impact was evaluated by behavioral tests and histological analyses and compared with APP23 mice to which Neumentix was not administered. The results showed that Neumentix administration increased the survival rate of APP23 mice and effectively reduced Aβ accumulation by enhancing its phagocytosis by microglial cells. These findings suggest that Neumentix is a potential natural nutritional treatment for improving the progression of AD.},
}

@article {pmid40466990,
year = {2025},
author = {Chen, G and Zhang, J and Dong, A and Xiao, L and Huang, P and Huang, T and Ye, Q and Huang, E},
title = {AXL-mediate GEF-H1 phosphorylation was involved in microglia synapse phagocytosis in 5xFAD mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115327},
doi = {10.1016/j.expneurol.2025.115327},
pmid = {40466990},
issn = {1090-2430},
abstract = {Studies indicated that microglial synapse phagocytosis played a critical role in synapse loss and pathogenesis in Alzheimer's disease. AXL was one of key phagocytic receptors and was upgraded in disease associated microglia. This study aimed to investigate the role of AXL-mediated microglial synapse phagocytosis in AD mice model. Our data indicated that AXL was increased in microglia in 5xFAD mouse AD model. The lentivirus PLV-CXC3CR1-shAXl was applied to especially knockdown the AXL expression in microglia and the shAXL treatment ameliorated the cognitive impairment in 5xFAD mice. AXL knockdown decreased the 6E10 positive amyloid plaques, the diffusion index of amyloid plaques and the level of phosphorylated Tau. shAXL treatment increased microglial complexity and reduced the microglial synapse phagocytosis. This study further demonstrated that GEF-H1 was identified as a substrate of AXL and mainly phosphorylated at Y470 by AXL. The AXL-mediated GEF-H1-Y470 phosphorylation enhanced the phagocytic capacity of BV2. It seems paradoxical that amyloid plaque load and microglial phagocytosis were both decreased at the same time when the AXL was knockdown, but these indicated that microglia phagocytosis related synapse loss played a more critical role in cognitive impairment and AD pathogenesis than amyloid plaque load. Our study demonstrated that the activated AXL in microglia in 5xFAD enhanced synapse phagocytosis via phosphorylating GEF-H1 at Y470, which led to synapse loss and cognitive impairment. The application of AXL blockage would be a potential therapeutic strategy for AD treatment.},
}

@article {pmid40466018,
year = {2025},
author = {Agosta, F and Cecchetti, G and Spinelli, EG and Ghirelli, A and Rugarli, G and Filippi, M},
title = {MRI protocols and sequences for amyloid-related imaging abnormalities monitoring in Alzheimer's disease patients treated with monoclonal antibodies.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
doi = {10.1097/WCO.0000000000001388},
pmid = {40466018},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: This review provides an updated overview of amyloid-related imaging abnormalities (ARIA) associated with antiamyloid monoclonal antibodies (mAbs) in Alzheimer's disease (AD). Following regulatory approvals for both lecanemab and donanemab in the United States, and pending decisions in Europe, standardized understanding of ARIA definitions, risk factors, and optimal MRI surveillance is increasingly important to guide treatment and ensure safety.

RECENT FINDINGS: ARIA, including vasogenic edema (ARIA-E) and microhemorrhages/siderosis (ARIA-H), are a frequent adverse event in patients receiving antiamyloid mAbs, particularly among APOE ε4 homozygotes. Incidence varies by agent and trial design. While often asymptomatic and self-limiting, ARIA can occasionally present with symptoms or recur. MRI, especially FLAIR and susceptibility-sensitive imaging, is essential for baseline risk stratification and monitoring. Key imaging biomarkers include microbleeds and superficial siderosis. Recent guidelines support genotyping and risk-adapted MRI protocols before and during therapy.

SUMMARY: ARIA reflect vascular vulnerability during amyloid clearance in AD. Their management requires close collaboration between neurologists and neuroradiologists, with harmonized MRI protocols and risk mitigation strategies critical for safe and effective use of disease-modifying therapies.},
}

@article {pmid40465608,
year = {2025},
author = {Liu, L and Li, Y and Yang, K},
title = {Dynamically weighted graph neural network for detection of early mild cognitive impairment.},
journal = {PloS one},
volume = {20},
number = {6},
pages = {e0323894},
doi = {10.1371/journal.pone.0323894},
pmid = {40465608},
issn = {1932-6203},
mesh = {*Cognitive Dysfunction/diagnosis/physiopathology ; Humans ; *Neural Networks, Computer ; Aged ; Early Diagnosis ; Alzheimer Disease/diagnosis/physiopathology ; Male ; Female ; Brain/physiopathology ; Magnetic Resonance Imaging ; Algorithms ; *Nerve Net/physiopathology ; Graph Neural Networks ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disease that primarily affects the elderly population. The early detection of mild cognitive impairment (MCI) holds significant clinical importance for prompt intervention and treatment of AD. Currently, functional connectivity (FC) networks-based diagnostic methods for early MCI (eMCI) detection are widely employed. FC considers the interaction patterns between brain regions as a topological structure. Recently, graph neural network (GNN) approaches have been utilized for disease diagnosis using FC networks, leveraging their ability to extract features from topological structures. However, existing methods typically treat FC features as GNN node attributes, disregarding the fact that FC features represent the weights of connection edges in FC networks with topological characteristics. In this paper, we propose a dynamically weighted GNN-based approach for early eMCI detection. Our method takes into account the topological structure and dynamic properties of FC networks by utilizing temporal FC features as the weighted adjacency matrix for dynamic GNNs. Moreover, the weighted graph local clustering coefficient of brain regions is employed as the node feature for GNNs. We extensively evaluated our approach using the ADNI database and achieved accuracies of 91.67% and 78.33% on low- and high-order FC networks, respectively. These results demonstrate the effectiveness and superiority of our proposed method compared to existing approaches.},
}

*Cognitive Dysfunction/diagnosis/physiopathology
Humans
*Neural Networks, Computer
Aged
Early Diagnosis
Alzheimer Disease/diagnosis/physiopathology
Male
Female
Brain/physiopathology
Magnetic Resonance Imaging
Algorithms
*Nerve Net/physiopathology
Graph Neural Networks

@article {pmid40464500,
year = {2025},
author = {Dedoni, S and Avdoshina, V and Olianas, MC and Onali, P},
title = {Role of Lysophosphatidic Acid in Neurological Diseases: From Pathophysiology to Therapeutic Implications.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {5},
pages = {28245},
doi = {10.31083/FBL28245},
pmid = {40464500},
issn = {2768-6698},
mesh = {Humans ; *Lysophospholipids/metabolism ; *Nervous System Diseases/physiopathology/metabolism/drug therapy ; Animals ; Receptors, Lysophosphatidic Acid/metabolism ; Signal Transduction ; },
abstract = {Lysophosphatidic acid (LPA), a bioactive lipid molecule, has been identified as a critical regulator of several cellular processes in the central nervous system, with significant impacts on neuronal function, synaptic plasticity, and neuroinflammatory responses. While Alzheimer's disease, Multiple Sclerosis, and Parkinson's disease have garnered considerable attention due to their incidence and socioeconomic significance, many additional neurological illnesses remain unclear in terms of underlying pathophysiology and prospective treatment targets. This review synthesizes evidence linking LPA's function in neurological diseases such as traumatic brain injury, spinal cord injury, cerebellar ataxia, cerebral ischemia, seizures, Huntington's disease, amyotrophic lateral sclerosis, Hutchinson-Gilford progeria syndrome, autism, migraine, and human immunodeficiency virus (HIV)-associated complications Despite recent advances, the specific mechanisms underlying LPA's actions in various neurological disorders remain unknown, and further research is needed to understand the distinct roles of LPA across multiple disease conditions, as well as to investigate the therapeutic potential of targeting LPA receptors in these pathologies. The purpose of this review is to highlight the multiple functions of LPA in the aforementioned neurological diseases, which frequently share the same poor prognosis due to a scarcity of truly effective therapies, while also evaluating the role of LPA, its receptors, and signaling as promising actors for the development of alternative therapeutic strategies to those proposed today.},
}

Humans
*Lysophospholipids/metabolism
*Nervous System Diseases/physiopathology/metabolism/drug therapy
Animals
Receptors, Lysophosphatidic Acid/metabolism
Signal Transduction

@article {pmid40464420,
year = {2025},
author = {Martínez Campos, E and Tellechea Aramburo, P and Sánchez Ruiz de Gordoa, J and Larumbe Ilundain, R},
title = {[Cerebrospinal Fluid Biomarker Profile in Atypical Alzheimer's Disease].},
journal = {Revista de neurologia},
volume = {80},
number = {4},
pages = {36399},
doi = {10.31083/RN36399},
pmid = {40464420},
issn = {1576-6578},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Female ; Aged ; Male ; Biomarkers/cerebrospinal fluid ; *tau Proteins/cerebrospinal fluid ; Retrospective Studies ; *Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Aged, 80 and over ; *Peptide Fragments/cerebrospinal fluid ; Phenotype ; },
abstract = {INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are essential for the early identification of non-amnestic phenotypes. Increased levels of total tau (t-tau) and phosphorylated tau (p-tau) have been reported in atypical AD cases, although the specific pattern remains a subject of debate. This study aimed to evaluate CSF biomarker profiles in relation to clinical phenotype.

MATERIALS AND METHODS: A retrospective review was performed, analyzing demographic data, time to diagnosis, clinical phenotype, and core AD biomarkers (beta-amyloid peptide 1-42 (Aβ1-42), t-tau, p-tau) in CSF from patients evaluated at University Hospital in Navarra between 2019 and 2022.

RESULTS: The study included 57 patients (54% female, mean age 67 years), of whom 41 met AD diagnostic criteria. Among these, 10 patients (25%) presented with atypical phenotypes (50% aphasic, 30% frontal, 20% mixed non-amnestic). Compared with the amnestic phenotype, the atypical group exhibited significantly higher t-tau (562.9 pg/mL vs 320.3 pg/mL, p = 0.021) and p-tau (81.5 pg/mL vs 37.7 pg/mL, p = 0.016) levels, independent of age, sex, and time to diagnosis.

CONCLUSIONS: Atypical cases demonstrated increased tau levels, suggesting earlier and more extensive cortical damage than the amnestic phenotype. These findings underscore the significance of CSF biomarkers in phenotypic differentiation, disease course prediction, and individualized treatment strategies for AD.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/diagnosis
Female
Aged
Male
Biomarkers/cerebrospinal fluid
*tau Proteins/cerebrospinal fluid
Retrospective Studies
*Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
Aged, 80 and over
*Peptide Fragments/cerebrospinal fluid
Phenotype

@article {pmid40464332,
year = {2025},
author = {Naim, A and Farooqui, AM and Badruddeen, and Khan, MI and Akhtar, J and Ahmad, A and Islam, A},
title = {The Role of Kinases in Neurodegenerative Diseases: From Pathogenesis to Treatment.},
journal = {The European journal of neuroscience},
volume = {61},
number = {11},
pages = {e70156},
doi = {10.1111/ejn.70156},
pmid = {40464332},
issn = {1460-9568},
mesh = {Humans ; *Neurodegenerative Diseases/enzymology/drug therapy/metabolism ; Animals ; *Protein Kinases/metabolism ; Protein Kinase Inhibitors/therapeutic use ; },
abstract = {Neurodegenerative diseases are characterized by progressive neuronal loss and dysfunction, with protein kinases playing crucial roles in their pathogenesis. This article explores the involvement of protein kinases in these disorders, focusing on their contributions to disease mechanisms, potential as therapeutic targets and challenges in developing effective treatments. In Alzheimer's disease, kinases such as CDK5, GSK3β and MARK4 are implicated in tau hyperphosphorylation and the formation of neurofibrillary tangles. Kinases also regulate amyloid-β processing and plaque formation. In Parkinson's disease, LRRK2, PINK1 and other kinases contribute to α-synuclein pathology, mitochondrial dysfunction and neuroinflammation. LRRK2 inhibitors and PROTACs have shown promise in preclinical models. Huntington's disease involves altered kinase activity, with CK2, GSK3 and MAPK pathways influencing mutant huntingtin toxicity and aggregation. Kinases are also implicated in less common neurodegenerative diseases, such as ALS and spinocerebellar ataxias. Despite the therapeutic potential of targeting kinases, challenges remain, including the complexity of kinase networks, blood-brain barrier permeability and the lack of robust biomarkers. Emerging technologies, such as covalent inhibitors, targeted protein degradation and combination therapies, offer new avenues for addressing these challenges and developing more effective treatments for neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/enzymology/drug therapy/metabolism
Animals
*Protein Kinases/metabolism
Protein Kinase Inhibitors/therapeutic use

@article {pmid40464180,
year = {2025},
author = {Khabibov, M and Garifullin, A and Sadreeva, A and Fernandez, MF and Kashaev, M and Topchu, I and Kharin, L and Boumber, Y},
title = {Functional and Clinical Relevance of the Crosstalk between the Glymphatic System and the Lymphatic System.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X359861250224051857},
pmid = {40464180},
issn = {1875-6190},
abstract = {In this review, we describe the concept of the glymphatic system as a glial-dependent clearance pathway in the brain. The hypothesis of the glymphatic system function suggests that dural lymphatic vessels absorb the cerebrospinal fluid and brain interstitial fluid via the glymphatic system and transport fluid into deep cervical lymph nodes. We present the accumulated data of various studies confirming the possible interconnection among the brain interstitial fluid, cerebrospinal fluid, and the glymphatic system. Anatomical features are discussed here together with a possible variety of glymphatic system functions, including the removal of waste products, transport of substances, and immune function. The glymphatic system is hypothesized to be involved in pathogenesis of many diseases, including Alzheimer's disease, stroke, and Parkinson's disease. We also discuss the role of the glymphatic system in pathophysiology and the complications of brain tumors. Meningeal lymphatics is thoroughly analyzed as well. Finally, we propose new treatment approaches to brain tumors, Parkinson's disease, and stroke using cervical lymph nodes and backward fluid flow in the meningeal lymphatic vessels.},
}

@article {pmid40463636,
year = {2025},
author = {Iulita, MF and Streel, E and Harrison, J},
title = {Digital biomarkers: Redefining clinical outcomes and the concept of meaningful change.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70114},
pmid = {40463636},
issn = {2352-8737},
abstract = {UNLABELLED: MCID (minimal clinically important difference) is a patient-centered concept used in clinical research that represents the smallest change that someone living with Alzheimer's disease would identify as important. There are several challenges associated with the universal application of this construct. Alzheimer's disease progresses differently for each individual, complicating the establishment of a universal standard that accounts for individual-level issues. Alzheimer's disease is also a gradual and evolving disorder, and what is perceived as clinically meaningful can vary significantly at early and late disease stages. People living with Alzheimer's disease and caregivers may have differing perspectives on the benefits of treatment outcomes, making it more challenging to establish an appropriate MCID. Moreover, Alzheimer's trials rely on a variety of tests to evaluate cognitive and functional impairments. However, these tests often lack sensitivity to early-stage changes and are affected by variability in rater rankings. Digital biomarkers and advanced health technologies have emerged as a hot topic in modern medicine. They offer a promising approach for detecting real-time, objective clinical differences and improving patient outcomes by enabling continuous monitoring, individualized assessments, and leveraging artificial intelligence learning for complex analytical predictions. However, while these advancements hold great potential, they also raise important considerations around standardization, accuracy, and integration into current clinical frameworks. As new technologies are introduced alongside evolving regulatory frameworks, the primary focus must remain on outcomes that truly matter to people living with Alzheimer's disease and their caregivers, ensuring that the principle of clinical meaningfulness is not lost.

HIGHLIGHTS: Minimal clinically important difference (MCID) represents the smallest change in a patient's condition that would be considered meaningful, but defining this for Alzheimer's disease is challenging due to its heterogeneity.The perception of what is clinically meaningful may differ at the individual level, at different disease stages within the same individual, and between patient and caregiver.Traditional tests used as endpoints in Alzheimer's trials lack the sensitivity to detect subtle changes and are limited by range restrictions, making them less effective for accurately capturing treatment efficacy.Digital biomarkers and artificial intelligence (AI)-driven health technologies may offer the potential to enhance the detection of clinically meaningful changes by providing continuous, objective monitoring and advanced analytics for individualized patient assessments.Both the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) are playing pivotal roles in advancing the use of digital health technologies, facilitating the evolution of regulatory frameworks to ensure these innovations are effectively integrated into clinical research and practice.},
}

@article {pmid40463529,
year = {2025},
author = {Gauron, MC and Prokopenko, D and Lee, S and Wolfe, SA and Hecker, J and Willett, J and Waqas, M and Lordén, G and Yang, Y and Mayfield, JE and Castanho, I and Mullin, K and Morgan, S and Hahn, G and Demeo, DL and Hide, W and Bertram, L and Lange, C and Newton, AC and Tanzi, RE},
title = {Protein kinase C eta enhances Golgi-localized signaling and is associated with Alzheimer's disease using a recessive mode of inheritance.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.13.25327562},
pmid = {40463529},
abstract = {UNLABELLED: The identification of Alzheimer's disease (AD)-associated genomic variants has provided powerful insight into disease etiology. Genome-wide association studies (GWAS) for AD have successfully identified new targets but have almost exclusively utilized additive genetic models. Here, we performed a family-based GWAS under a recessive inheritance model using whole genome sequencing from families affected by AD. We found that the variant, rs7161410, located in an intron of the PRKCH gene, encoding protein kinase C eta (PKCη), was associated with AD risk (p-value=1.41 × 10-7). Further analysis revealed a rare PRKCH missense mutation K65R in linkage disequilibrium with rs7161410, which was present in homozygous carriers of the rs7161410 risk allele. We show that this mutation leads to enhanced localization and signaling of PKCη at the Golgi. The novel genetically-validated association of aberrant PKCη signaling with AD opens avenues for new therapeutic targets aimed at prevention and treatment.

ONE SENTENCE SUMMARY: Protein kinase C eta enhances Golgi-localized signaling and is associated with Alzheimer's disease.},
}

@article {pmid40463120,
year = {2025},
author = {Kinreich, S and Bingly, A and Pandey, G},
title = {Alzheimer's subtypes A supervised, unsupervised, multimodal, multilayered embedded recursive (SUMMER) AI study.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.09.653177},
pmid = {40463120},
issn = {2692-8205},
abstract = {Since Alzheimer's disease (AD) is a heterogeneous disease, different subtypes may have distinct biological, genetic, and clinical characteristics, requiring tailored interventions. While several proposed subtypes of AD exist, there is still no clear consensus on a definitive classification. By leveraging complementary AI approaches, including supervised and unsupervised learning, within a recursive pipeline (SUMMER) that integrates multimodal datasets encompassing MRI measurements, phenotypes, and genetic data, our goal was to generate robust scientific evidence for identifying AD subtypes. Data was downloaded from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and included neuroimaging data (MRI), genetics (SNPs), clinical diagnosis, and demographics. 1133 European American participants' images, aged 55-95, were included in this study. The analysis was multi-fold, where the first step involved applying an unsupervised application to a subset of the MRI sample (AD + cognitively normal (CN) aged matched groups, 100 men aged 68-85 years, and 76 women aged 68-85 years). The MRI brain gray matter was segmented into 44 regions of interest (ROIs) according to a standard atlas, and 618 features were extracted, including ROI voxel intensity measurements such as minimum, maximum, and histogram variables. Results identified a cluster of subtype AD men and a cluster of subtype AD women that were distinct from the rest of their respective samples. In the next step, the integrity of the identified subtype AD clusters was investigated using the XGBoost supervised machine learning application with genetic features (SNPs, N=36,724) and labels: the identified subtype AD cluster vs. the rest of the sample, stratified by sex. A significant AD subtype men model (accuracy=0.85, F1=0.72, AUC=0.83) and a significant women AD subtype model (accuracy=0.81, F1=0.81, AUC=0.81) were built, confirming the homogeneity of the isolated AD subtype clusters. Discriminative biomarkers were extracted from the significant models, including selected ROIs and SNPs. Finally, the subtype models were tested on an unseen subset of ADNI data. The genetic-based models identified clusters of AD subtype participants consisting of 34% of the men AD group and 47% of the women AD group. Phenotypic analysis indicates that lower body weight was associated with the women's AD subtype. Complex diseases like AD demand a sophisticated, multimodal approach for precise diagnosis. Effectively identifying disease subtypes enhances the potential for personalized treatment, ultimately improving patient outcomes.},
}

@article {pmid40462117,
year = {2025},
author = {Akif, A and Nguyen, TTM and Liu, L and Xu, X and Kulkarni, A and Jiang, J and Zhang, Y and Hao, J},
title = {Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.},
journal = {Fluids and barriers of the CNS},
volume = {22},
number = {1},
pages = {55},
pmid = {40462117},
issn = {2045-8118},
support = {R21NS133895-01//National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS105787//National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors/metabolism/drug effects ; Mice ; *Dementia, Vascular/drug therapy/metabolism ; *Signal Transduction/drug effects ; *Sulfonylurea Compounds/pharmacology ; *Cognitive Dysfunction/drug therapy/metabolism ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Carotid Stenosis/complications ; Brain/drug effects/metabolism ; },
abstract = {BACKGROUND: As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.

METHODS: In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50th day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA.

RESULTS: AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood.

CONCLUSIONS: The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.

CLINICAL TRIAL NUMBER: Not applicable.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors/metabolism/drug effects
Mice
*Dementia, Vascular/drug therapy/metabolism
*Signal Transduction/drug effects
*Sulfonylurea Compounds/pharmacology
*Cognitive Dysfunction/drug therapy/metabolism
Male
Disease Models, Animal
Mice, Inbred C57BL
Carotid Stenosis/complications
Brain/drug effects/metabolism

@article {pmid40461729,
year = {2025},
author = {Lashgari, NA and Khalaji, M and Rana, P and Badrabadi, F and Rahnama, M and Nasoori, H and Momeni Roudsari, N and Khosravi Nia, MM and Shafaroodi, H},
title = {Psychedelics in the Treatment of Neurologic and Psychiatric Disorders: Coincidence or a New Point of View.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40461729},
issn = {1559-1182},
abstract = {Neurological and psychiatric disorders are considered one of the major problems of today's societies and cause many individual and social problems. Current treatments are effective, but due to their burdens, there is always an effort to introduce novel treatments. Psychedelics, a diverse group of psychoactive compounds, including LSD, psilocybin, DMT, MDMA, and ketamine, have shown potential in modulating neurologic and psychiatric disorders due to several mechanisms. This review investigates the therapeutic potential of psychedelics in both neurologic and neuropsychiatric disorders due to their several mechanisms such as anti-inflammatory, anti-oxidative, and biological properties. This study was conducted across major databases, such as PubMed, Scopus, Web of Science, Google Scholar, and Medline, due to the systematically searched literature including clinical, preclinical, and in vitro studies. Psychedelic compounds such as psilocybin, LSD, and MDMA have demonstrated beneficial effects across various models of neuropsychiatric and neurologic disorders, including depression, PTSD, Alzheimer's disease, and Parkinson's disease. These effects are mediated through multiple mechanisms, including anti-inflammatory actions (e.g., downregulation of cytokines such as IL-6 and TNF-α), antioxidant activity (e.g., induction of SOD), and enhancement of neuroplasticity through increased expression of brain-derived neurotrophic factor such as BDNF. Additionally, psychedelics modulate key neurotransmitter systems, notably increasing synaptic levels of serotonin and dopamine, which are critically involved in mood regulation and cognitive function. Compared to conventional treatments, psychedelics offer faster onset, durable effects, and possible disease-modifying properties, making them promising candidates for future neurotherapeutics.},
}

@article {pmid40461556,
year = {2025},
author = {Spencer, M and Kulbe, JR and Venkatesh, V and Laird, A and Ford, M and O'Brien, S and Boustani, A and Schlachetzki, JCM and Fields, JA},
title = {Caloric restriction mimetic 2-deoxyglucose alters metabolic and transcriptomic phenotype in association with changes in chromatin accessibility in human astrocytes.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {19368},
pmid = {40461556},
issn = {2045-2322},
support = {MH134401/MH/NIMH NIH HHS/United States ; MH128108/MH/NIMH NIH HHS/United States ; },
mesh = {Humans ; *Astrocytes/metabolism/drug effects ; *Deoxyglucose/pharmacology ; *Chromatin/metabolism/drug effects ; *Transcriptome/drug effects ; Glycolysis/drug effects ; *Caloric Restriction ; 3-Hydroxybutyric Acid/pharmacology/metabolism ; Glucose/metabolism ; Interleukin-1beta/pharmacology ; Cells, Cultured ; Cytokines/metabolism ; },
abstract = {Caloric restriction and ketogenic diets may modify the progression of neurological disorders, including HIV-associated neurological disorders and Alzheimer's disease, in part by influencing astrocyte function. This study examines how metabolic substrate availability affects metabolic processes and gene expression in human astrocytes. We exposed astrocytes to the glycolysis inhibitor 2-deoxyglucose (2-DG), to mimic caloric restriction, prior to stimulation with interleukin-1β and measured extracellular flux using the Seahorse ® platform. We next analyzed gene expression and chromatin accessibility changes using RNA-sequencing and ATAC-sequencing, respectively. Finally, we tested the effects of glucose deprivation and the ketone body β-hydroxybutyrate (BHB) on inflammatory gene expression. 2-DG reduced oxygen consumption rate and extracellular acidification rate in the presence of IL-1β, while concomitantly decreasing expression of pro-inflammatory cytokines TNF, IL-6, and C3. These changes were linked to altered chromatin structure. The metabolic substrate β-hydroxybutyrate was associated with reduced cytokine expression compared to glucose. Inhibition of glycolysis attenuated IL-1β-induced inflammation and gene expression changes and altered chromatin architecture. Both glucose deprivation and BHB treatment reduced inflammatory cytokine expression, with additive effects when combined with 2-DG. These results suggest that targeting glycolysis could provide therapeutic strategies for treating neurological diseases through modulation of astrocyte-driven inflammation.},
}

Humans
*Astrocytes/metabolism/drug effects
*Deoxyglucose/pharmacology
*Chromatin/metabolism/drug effects
*Transcriptome/drug effects
Glycolysis/drug effects
*Caloric Restriction
3-Hydroxybutyric Acid/pharmacology/metabolism
Glucose/metabolism
Interleukin-1beta/pharmacology
Cells, Cultured
Cytokines/metabolism

@article {pmid40461232,
year = {2025},
author = {Yan, MH and Cai, H and Ding, HX and Su, SJ and Li, XN and Xu, ZQ and Feng, WC and Wu, QQ and Chen, JX and Wang, H and Wang, Q},
title = {[Multifaceted mechanisms of Danggui Shaoyao San in ameliorating Alzheimer's disease based on transcriptomics and metabolomics].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {8},
pages = {2229-2236},
doi = {10.19540/j.cnki.cjcmm.20241212.702},
pmid = {40461232},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Male ; *Drugs, Chinese Herbal/administration & dosage ; Mice ; Mice, Inbred C57BL ; Metabolomics ; *Transcriptome/drug effects ; Maze Learning/drug effects ; Hippocampus/drug effects/metabolism ; Humans ; Disease Models, Animal ; Memory/drug effects ; },
abstract = {This study explored the potential therapeutic targets and mechanisms of Danggui Shaoyao San(DSS) in the prevention and treatment of Alzheimer's disease(AD) through transcriptomics and metabolomics, combined with animal experiments. Fifty male C57BL/6J mice, aged seven weeks, were randomly divided into the following five groups: control, model, positive drug, low-dose DSS, and high-dose DSS groups. After the intervention, the Morris water maze was used to assess learning and memory abilities of mice, and Nissl staining and hematoxylin-eosin(HE) staining were performed to observe pathological changes in the hippocampal tissue. Transcriptomics and metabolomics were employed to sequence brain tissue and identify differential metabolites, analyzing key genes and metabolites related to disease progression. Reverse transcription-quantitative polymerase chain reaction(RT-qPCR) was employed to validate the expression of key genes. The Morris water maze results indicated that DSS significantly improved learning and cognitive function in scopolamine(SCOP)-induced model mice, with the high-dose DSS group showing the best results. Pathological staining showed that DSS effectively reduced hippocampal neuronal damage, increased Nissl body numbers, and reduced nuclear pyknosis and neuronal loss. Transcriptomics identified seven key genes, including neurexin 1(Nrxn1) and sodium voltage-gated channel α subunit 1(Scn1a), and metabolomics revealed 113 differential metabolites, all of which were closely associated with synaptic function, oxidative stress, and metabolic regulation. RT-qPCR experiments confirmed that the expression of these seven key genes was consistent with the transcriptomics results. This study suggests that DSS significantly improves learning and memory in SCOP model mice and alleviates hippocampal neuronal pathological damage. The mechanisms likely involve the modulation of synaptic function, reduction of oxidative stress, and metabolic balance, with these seven key genes serving as important targets for DSS in the treatment of AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/genetics
Male
*Drugs, Chinese Herbal/administration & dosage
Mice
Mice, Inbred C57BL
Metabolomics
*Transcriptome/drug effects
Maze Learning/drug effects
Hippocampus/drug effects/metabolism
Humans
Disease Models, Animal
Memory/drug effects

@article {pmid40460567,
year = {2025},
author = {Li, R and Huang, G and Chen, Y and Wang, X and Alty, J and Bai, Q},
title = {Evaluating the impact of human expertise in human-centered AI: A case study on finger-tapping video analysis for dementia detection.},
journal = {Computers in biology and medicine},
volume = {194},
number = {},
pages = {110468},
doi = {10.1016/j.compbiomed.2025.110468},
pmid = {40460567},
issn = {1879-0534},
abstract = {PURPOSE: Human-centered artificial intelligence (AI) plays a crucial role in medical research. This paper evaluates the impact of human expertise in AI systems, using dementia prediction as a case study. Specifically, plasma phospho-tau181 (ptau181) is employed as the ground truth for Alzheimer's disease (AD) to advance early detection and treatment strategies.

METHODS: In this empirical study, we investigated three distinct cases to explore AI's role in predicting ptau181 levels through finger-tapping analysis. Case 1 employed explicit features from finger movements combined with a Ridge regression model, emphasizing the interpretability enabled by human-engineered features. Case 2 introduced temporal dynamics using Long Short-Term Memory (LSTM) networks with displacement-vs-time data, highlighting how human experts can integrate temporal dependencies into AI models. Case 3 utilized a 3D Convolutional Neural Network (CNN) to autonomously extract temporal and spatial features from processed video data, showcasing AI's ability to learn and adapt with minimal human intervention.

RESULTS: Evaluation demonstrated Case 3's superior performance, illustrating the trade-offs between model effectiveness and human involvement. Case 1 provided interpretability through explicit feature engineering, while Case 2 introduced complexity with temporal dependencies.

CONCLUSION: This study underscores the crucial role of human-centered AI in medical research, particularly in predictive modeling for AD. By combining human expertise with advanced AI capabilities, we can unlock new avenues for early diagnosis and intervention, thereby advancing our understanding and treatment of complex AD conditions to improve patient outcomes.},
}

@article {pmid40460451,
year = {2025},
author = {Nishioka, K and Kawamura, M and Iima, M and Ueda, D and Ito, R and Saida, T and Kurokawa, R and Takumi, K and Sakata, A and Ide, S and Honda, M and Yanagawa, M and Sugawara, S and Oda, S and Watabe, T and Sofue, K and Hirata, K and Naganawa, S},
title = {The glymphatic system in oncology: from the perspective of a radiation oncologist.},
journal = {Journal of radiation research},
volume = {},
number = {},
pages = {},
doi = {10.1093/jrr/rraf027},
pmid = {40460451},
issn = {1349-9157},
abstract = {The brain and spinal cord, which constitute the central nervous system, were historically considered immune-privileged sites, as it was believed they lacked an equivalent to the systemic lymphatic system. However, in 2013, a pathway facilitating the clearance of waste products through the brain parenchyma via the perivascular space was proposed, garnering attention as the 'glymphatic system'. Similar to the systemic lymphatic system, the glymphatic system plays a critical role in immune responses and has been implicated not only in Alzheimer's disease and inflammatory brain disorders but also in conditions such as hydrocephalus and glaucoma, which are associated with cerebrospinal fluid circulation impairments. Recent studies have suggested that dysfunction of the glymphatic system may promote the progression of brain tumors and reduce the efficacy of immune responses and pharmacological therapies targeting tumors. Radiotherapy is a major treatment option for brain tumors; however, while it can enhance immune responses against tumors, it may also suppress these responses at the same time. Additionally, cranial irradiation has been suggested to impair the function of the glymphatic system. This review provides an overview of the structure and functional evaluation methods of the glymphatic system, summarizes the effects of its dysfunction on brain tumor treatment, and explores recent findings on the impact of radiation therapy on glymphatic system functioning. Lastly, it also explores the potential for radiation therapy strategies that account for their effects on the glymphatic system.},
}

@article {pmid40459816,
year = {2025},
author = {Vismara, M and Trivigno, SMG and Zarà, M and Momi, S and Gresele, P and Camera, M and Canobbio, I and Guidetti, GF and Torti, M},
title = {Platelet hyperreactivity and frailty in a mouse model of Alzheimer's disease are prevented by anti-oxidant treatment.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {40459816},
issn = {2509-2723},
support = {Grant n 2018-0483//Fondazione Cariplo/ ; },
abstract = {Frailty is an age-related syndrome commonly associated with different comorbidities, and its occurrence is particularly frequent in patients with Alzheimer's disease (AD). A persisting low-grade inflammation has been suggested to favor the onset of both AD and frailty. Besides their role in hemostasis and thrombosis, blood platelets are true inflammatory cells, and their direct contribution to the onset and progression of AD has been documented. In this work, we investigated whether platelet hyperreactivity and pro-oxidative functions are implicated in the development of frailty in a mouse model of AD, the APP23 mice. Assessment of 31 specific clinical signs of deterioration in mice at 3, 9, and 18 months of age demonstrated that the development of frailty was significantly more pronounced in the APP23 mice compared to wild-type littermates. In 18-month-old APP23 mice, a significant platelet hyperreactivity was detected as shown by a significantly stronger platelet aggregation in response to submaximal stimulation of both collagen and thrombin receptors. Moreover, the pro-inflammatory function of platelets, evaluated as circulating and agonist-induced platelet-neutrophil aggregate formation, was significantly increased in aged APP23 mice compared to wild-type littermates. Platelet hyperreactivity was partially prevented by prolonged treatment with the anti-oxidant agent Tempol, which reduced both agonist-induced aggregation and platelet-neutrophil aggregate formation. Importantly, prolonged treatment of APP23 mice with Tempol significantly reduced also the frailty index score in 18-month-old animals. These results outline the possible beneficial effect of an anti-oxidant treatment in hampering platelet hyperreactivity and preventing the onset of frailty associated to AD.},
}

@article {pmid40459787,
year = {2025},
author = {Chen, CD and Franklin, EE and Li, Y and Joseph-Mathurin, N and Burns, AL and Hobbs, DA and McCullough, AA and Schultz, SA and Xiong, C and Wang, G and Masellis, M and Hsiung, GR and Gauthier, S and Berman, SB and Roberson, ED and Honig, LS and Clarnette, R and Ringman, JM and Galvin, JE and Brooks, W and Suzuki, K and Black, S and Levin, J and Aggarwal, NT and Jucker, M and Frosch, MP and Kofler, JK and White, C and Keene, CD and Chen, J and Daniels, A and Gordon, BA and Ibanez, L and Karch, CM and Llibre-Guerra, J and McDade, E and Morris, JC and Supnet-Bell, C and Allegri, RF and Lee, JH and Day, GS and Lopera, F and Roh, JH and Schofield, PR and Mills, S and Benzinger, TLS and Bateman, RJ and Perrin, RJ and , and , },
title = {Immunohistochemical evaluation of a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease.},
journal = {Acta neuropathologica},
volume = {149},
number = {1},
pages = {57},
pmid = {40459787},
issn = {1432-0533},
support = {U19AG032438/NH/NIH HHS/United States ; },
mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/genetics/metabolism ; Male ; Female ; Amyloid beta-Peptides/metabolism ; Aged ; *Brain/pathology/drug effects/metabolism ; Middle Aged ; Immunohistochemistry ; Aged, 80 and over ; },
abstract = {Clinical trials of anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer disease (AD) infer target engagement from Aβ positron emission tomography (PET) and/or fluid biomarkers such as cerebrospinal fluid (CSF) Aβ42/40. However, these biomarkers measure brain Aβ deposits indirectly and/or incompletely. In contrast, neuropathologic assessments allow direct investigation of treatment effects on brain Aβ deposits-and on potentially myriad 'downstream' pathologic features. From a clinical trial of anti-Aβ monoclonal antibodies in dominantly inherited AD (DIAD), in the largest study of its kind, we measured immunohistochemistry area fractions (AFs) for Aβ deposits (10D5), tauopathy (PHF1), microgliosis (IBA1), and astrocytosis (GFAP) in 10 brain regions from 10 trial cases-gantenerumab (n = 4), solanezumab (n = 4), placebo/no treatment (n = 2)-and 10 DIAD observational study cases. Strikingly, in proportion to total drug received, Aβ deposit AFs were significantly lower in the gantenerumab arm versus controls in almost all areas examined, including frontal, temporal, parietal, and occipital cortices, anterior cingulate, hippocampus, caudate, putamen, thalamus, and cerebellar gray matter; only posterior cingulate and cerebellar white matter comparisons were non-significant. In contrast, AFs of tauopathy, microgliosis, and astrocytosis showed no differences across groups. Our results demonstrate with direct histologic evidence that gantenerumab treatment in DIAD can reduce parenchymal Aβ deposits throughout the brain in a dose-dependent manner, suggesting that more complete removal may be possible with earlier and more aggressive treatment regimens. Although AFs of tauopathy, microgliosis, and astrocytosis showed no clear response to partial Aβ removal in this limited autopsy cohort, future examination of these cases with more sensitive techniques (e.g., mass spectrometry) may reveal more subtle 'downstream' effects.},
}

Humans
*Antibodies, Monoclonal, Humanized/therapeutic use
*Alzheimer Disease/drug therapy/pathology/genetics/metabolism
Male
Female
Amyloid beta-Peptides/metabolism
Aged
*Brain/pathology/drug effects/metabolism
Middle Aged
Immunohistochemistry
Aged, 80 and over

@article {pmid40459315,
year = {2025},
author = {Moghekar, AR},
title = {Clinical Features and Diagnosis of Normal Pressure Hydrocephalus.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {31},
number = {3},
pages = {790-812},
pmid = {40459315},
issn = {1538-6899},
mesh = {Humans ; *Hydrocephalus, Normal Pressure/diagnosis/complications/surgery ; Male ; Aged ; Female ; Gait Disorders, Neurologic/etiology ; },
abstract = {OBJECTIVE: This article serves as a practical guide for the assessment of patients with suspected idiopathic normal pressure hydrocephalus (NPH).

LATEST DEVELOPMENTS: Significant advancements in neuroimaging, biomarker identification, and neurosurgical techniques have considerably improved the diagnostic accuracy and outcomes of treatment for idiopathic NPH. The full triad of gait disturbance, cognitive impairment, and urinary incontinence is not present in all patients and is not a prerequisite to pursuing treatment. Comorbid cervical stenosis is common and may also require surgical intervention.

ESSENTIAL POINTS: NPH remains a challenging clinical entity with significant overlap in presentation with other neurodegenerative disorders such as Alzheimer disease, vascular dementia, and parkinsonian syndromes, especially progressive supranuclear palsy and dementia with Lewy bodies. Gait tends to be affected first and more severely than other domains in patients with idiopathic NPH. The CSF tap test is a key diagnostic tool where both objective and subjective improvements in symptoms help identify patients likely to have a good outcome after shunt surgery.},
}

Humans
*Hydrocephalus, Normal Pressure/diagnosis/complications/surgery
Male
Aged
Female
Gait Disorders, Neurologic/etiology

@article {pmid40458441,
year = {2025},
author = {Hawiset, T and Sriraksa, N and Anukanon, S and Kamsrijai, U and Praman, S and Teerapattarakan, N and Inkaew, P},
title = {Tacca chantrieri André Rhizome Extract Alleviates Scopolamine-Induced Cognitive Impairment and Neuroinflammation in Rats.},
journal = {Advances in pharmacological and pharmaceutical sciences},
volume = {2025},
number = {},
pages = {7334303},
pmid = {40458441},
issn = {2633-4690},
abstract = {Tacca chantrieri André is a native plant from Northern Thailand with reported pharmacological effects, including antioxidant, anti-inflammatory, and neuroprotective properties. This study investigated the neuroinflammatory and cognitive-enhancing effects of Tacca chantrieri André rhizome extract (TCE) in a scopolamine-injected model, which mimics an Alzheimer's disease (AD) animal model. Animals were divided into six groups: (1) a control group, (2) a vehicle-treated group, (3) a donepezil-treated group (3 mg/kg BW) as a positive control, and (4-6) three TCE-treated groups receiving 50, 100, or 200 mg/kg BW once daily for 14 days. Starting on Day 8, animals received daily intraperitoneal injections of scopolamine (3 mg/kg BW) for 7 consecutive days to induce cognitive impairment. On day 14, behavioral tests were conducted, including the Y-maze and open field tests. On day 15, animals were euthanized, and their brains were collected for Nissl staining, immunofluorescence staining, and biochemical analyses using an ELISA kit. Our results demonstrated that TCE treatment attenuated scopolamine-induced memory deficits and neuroinflammation. Specifically, TCE administration reduced levels of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and decreased glial fibrillary acidic protein (GFAP) expression in the hippocampus. Additionally, TCE improved neuronal survival and enhanced serotonin levels, contributing to cognitive improvements. The qualitative analysis of TCE using LC-QTOF-MS identified various chemical constituents, including saponins, flavonoids, and phenolic compounds. These bioactive compounds contributed to the neuroprotective effects of TCE by modulating neuroinflammation and cognitive function. The neuroprotective effects of TCE suggested its potential as a therapeutic agent for memory impairment associated with AD.},
}

@article {pmid40457983,
year = {2025},
author = {Shikha, R and Kumar, D and Lari, MQ and Ashesh, AM and Wal, P and Singh, B and Pandey, S and Kumar, D and Kumar, A},
title = {Unraveling Neurodegenerative Disorders: The Potential of Indole and Imidazole-Based Heterocycles.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266356937250527075734},
pmid = {40457983},
issn = {1873-4294},
abstract = {Neurodegenerative diseases present a considerable challenge to healthcare systems worldwide, prompting the exploration of innovative treatment strategies. Heterocyclic compounds, specifically those originating from the indole and imidazole structures, have garnered increasing interest due to their potential to protect neurons. Based on an in-depth literature survey in this review, we have compiled various derivatives of indole and imidazole scaffolds with potential in neurodegenerative disorders. This review also emphasized the Structure-Activity Relationship (SAR) and pharmacokinetics to reveal the active pharmacophores of various indole and imidazole analogs. We delve into the underlying molecular and cellular mechanisms involved in neurodegeneration, highlighting how indole and imidazole derivatives exert neuroprotective effects by modulating oxidative stress, inflammation, protein misfolding, inhibiting cholinesterase, and neuroinflammation. Finally, we address the challenges and prospects in translating these findings into clinical therapies, underscoring the need for continued research to optimize the safety and efficacy of heterocyclic compounds in the treatment of neurodegenerative disorders.},
}

@article {pmid40457432,
year = {2025},
author = {Du, L and Wang, B and Wang, X and Wang, L and Wang, R and Zhang, Y and Hong, Z and Han, X and Wang, Y},
title = {Gastrointestinal exposure to silica nanoparticles induced Alzheimer's disease-like neurotoxicity in mice relying on gut microbiota and modulation through TLR4/NF-κB and HDAC.},
journal = {Journal of nanobiotechnology},
volume = {23},
number = {1},
pages = {406},
pmid = {40457432},
issn = {1477-3155},
mesh = {Animals ; *Gastrointestinal Microbiome/drug effects ; *Silicon Dioxide/toxicity/chemistry ; Mice ; *Nanoparticles/toxicity/chemistry ; *Alzheimer Disease/metabolism/chemically induced ; NF-kappa B/metabolism ; Mice, Inbred C57BL ; *Toll-Like Receptor 4/metabolism ; *Histone Deacetylases/metabolism ; Male ; Gastrointestinal Tract/drug effects ; Oxidative Stress/drug effects ; Brain/drug effects/metabolism ; Signal Transduction/drug effects ; },
abstract = {BACKGROUND: Silica nanoparticles (SiO2 NPs) are widely used in the food and pharmaceutical industries and dramatically increase the health risks associated with gastrointestinal exposure. However, the neurotoxicological effects and mechanisms of exposure to SiO2 NPs and their relationship with the gut microbiome require further in-depth investigation. Here, we performed a systematic assessment of the toxicity of gavage containing 20 nm SiO2 NPs to C57BL/6 J mice.

RESULTS: After 14 weeks administration, we comprehensively discovered that gastrointestinal exposure to SiO2 NPs led to mice Alzheimer's disease (AD)-like neurotoxicity, including Aβ accumulation, cognitive impairment, oxidative stress burden, and neuroinflammation, which was microbiota-gut-brain axis-dependent and proven using a low-load gut-bacteria experiment and antibiotic treatment. Mechanistically, gastrointestinal exposure to SiO2 NPs disrupted intestinal homeostasis. Specifically, the total faecal short-chain fatty acid (SCFA) levels were reduced as analysed by 16S rRNA gene sequencing and liquid chromatography mass-spectrometry (LC-MS) analysis. The reduced SCFA content damaged the integrity of gut-brain axis by increasing gut permeability, which may have caused metabolite redistribution, brain basement membrane dissolution, activated the neuroinflammation signalling pathway TLR4/NF-κB, and interfered with HDAC3 and HDAC1/OGG1 pathways.

CONCLUSIONS: We showed for the first time that gastrointestinal exposure to SiO2 NPs depends on the gut microbiome and causes neurological and cognitive impairment via gut-brain axis information transmission. These findings suggest that the gut microbiota, as a mediator between intestinal and brain information communications, contributes to gastrointestinal exposure to SiO2 NPs-induced neurotoxicity. The health risks of exposure to SiO2 NPs should be recognised, and addressing strategies should be extensively reconsidered.},
}

Animals
*Gastrointestinal Microbiome/drug effects
*Silicon Dioxide/toxicity/chemistry
Mice
*Nanoparticles/toxicity/chemistry
*Alzheimer Disease/metabolism/chemically induced
NF-kappa B/metabolism
Mice, Inbred C57BL
*Toll-Like Receptor 4/metabolism
*Histone Deacetylases/metabolism
Male
Gastrointestinal Tract/drug effects
Oxidative Stress/drug effects
Brain/drug effects/metabolism
Signal Transduction/drug effects

@article {pmid40457153,
year = {2025},
author = {Liu, B and Zhao, Q and Shi, Q and Xu, W and Shi, F and Yang, R and Zhou, X},
title = {Hypothermia Alleviates TBI-Induced Tau Hyperphosphorylation Through RBM3-Dependent GSK-3β and AMPK Pathways.},
journal = {Neurocritical care},
volume = {},
number = {},
pages = {},
pmid = {40457153},
issn = {1556-0961},
support = {LTGY23H090002//Natural Science Foundation of Zhejiang Province/ ; 81671262//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Traumatic brain injury (TBI) often results in tau hyperphosphorylation, a key pathological feature of neurodegenerative diseases such as Alzheimer's disease. Hypothermia (HT) is a promising therapeutic intervention for TBI, but the underlying molecular mechanisms remain unclear. This study investigates the role of RNA-binding motif protein 3 (RBM3) in mediating the neuroprotective effects of HT on tau phosphorylation and its involvement in glycogen synthase kinase 3 beta (GSK-3β) and AMP-activated protein kinase (AMPK) signaling.

METHODS: We used a TBI mouse model to assess the effects of HT on tau phosphorylation using Western blotting and immunohistochemistry. The phosphorylation status of GSK-3β (Ser9) and AMPK (Thr172) was also analyzed to explore key signaling pathways. RBM3 expression was modulated using RBM3 short hairpin RNA (knockdown) and adenovirus-RBM3 plasmid (overexpression) to determine its role in HT-induced changes in tau phosphorylation.

RESULTS: Hypothermia treatment significantly reduced tau hyperphosphorylation in TBI mice compared with controls. Western blotting revealed a significant increase in GSK-3β Ser9 phosphorylation (p < 0.01) and AMPK Thr172 phosphorylation (p < 0.05) in the HT group. Manipulation of RBM3 expression showed that both RBM3 knockdown and overexpression affected the extent of tau dephosphorylation mediated by HT. Specifically, RBM3 overexpression enhanced the protective effects of HT, whereas knockdown diminished its efficacy.

CONCLUSIONS: Our findings suggest that RBM3 is a crucial mediator of the neuroprotective effects of hypothermia in TBI, acting through modulation of GSK-3β and AMPK signaling pathways. These results provide new insights into the molecular mechanisms of TBI treatment and highlight RBM3 as a potential therapeutic target for neurodegenerative diseases associated with tauopathies. Limitations include the need for further validation in clinical models.},
}

@article {pmid40456307,
year = {2025},
author = {Blokland, A and Borghans, L and Hasselmo, M and Sambeth, A},
title = {The effect of biperiden on episodic memory: Testing the serial position effect.},
journal = {Neurobiology of learning and memory},
volume = {220},
number = {},
pages = {108065},
doi = {10.1016/j.nlm.2025.108065},
pmid = {40456307},
issn = {1095-9564},
abstract = {Biperiden (BIP), a muscarinic type 1 (M1) receptor antagonist, has been proposed as a pharmacological model for episodic memory impairment in mild cognitive impairment (MCI) and early stages of Alzheimer's disease (AD). Understanding the effects of BIP on memory could also be relevant for the development of M1 agonists to improve memory. In this study, we specifically examined how BIP affected the serial position effect (SPE) in a word learning task. Since MCI and AD show memory deficits for the first words of a list (primacy effect) we predicted a similar effect for BIP. Data from four previous studies were collated in which the effects of BIP or placebo treatment was tested a double-blind randomized design. For testing the SPE effect, we calculated the average of the first 3 words (primacy), the last 3 words (recency) and the middle 10 words. To control for the level of performance in the different studies, z-scores were calculated. Overall, the analyses revealed a clear SPE effect. BIP did not impair the primacy or recency effect but was found to impair the memory for the middle 10 words in the delayed recall test. These findings indicate that blocking the M1 receptor not does impair the primacy or the recency effect in the SPE. Although BIP treatment has an overall impairing effect on episodic memory, it does not model primacy effect deficits in MCI and AD. However, M1 receptors appear to modulate the memory for weakly encoded/stored information suggesting that M1 agonist could improve verbal episodic memory.},
}

@article {pmid40455354,
year = {2025},
author = {Zhou, Y and Diwu, YC and Li, YX and Zhang, JY and Zhang, XX and Li, SF and Sun, T and Zhang, Q},
title = {Neuroprotective Effects of Tectoridin in H2O2-Induced Oxidative Stress and an Amyloid-Infused Rat Model of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {50},
number = {3},
pages = {179},
pmid = {40455354},
issn = {1573-6903},
support = {2023-YBSF-615//Key Research and Development Project of Shaanxi Province/ ; 22JS010//Key Scientific Research Project of Shaanxi Provincial Department of Education/ ; SZYKJCYC-2023-064//Scientific Research Project of Traditional Chinese Medicine Administration of Shaanxi Province/ ; L2023-CXNL-CXRC-014//nnovative Service Ability Support Plan of Xianyang City (Scientific and Technological Innovation Talents)/ ; S202310716079//Training Program of Innovation and Entrepreneurship for Undergraduates of Shaanxi University of Chinese Medicine/ ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; *Amyloid beta-Peptides/toxicity ; PC12 Cells ; Male ; *Hydrogen Peroxide/toxicity ; Peptide Fragments/toxicity ; Rats, Sprague-Dawley ; Disease Models, Animal ; Cell Survival/drug effects ; Apoptosis/drug effects ; },
abstract = {This study aims to examine the effects of tectoridin in both in vitro and in vivo models of Alzheimer's disease. In vitro, oxidative stress was induced in PC12 cells using 400 µM of hydrogen peroxide (H2O2) to simulate cellular damage. In vivo, a rat model of Alzheimer's disease was established through repeated intracerebroventricular administration of soluble amyloid-beta (Aβ1-42) to induce neurodegeneration. The effects of tectoridin on oxidative stress markers and protein expression levels were assessed. Tectoridin treatment significantly improved cell survival and enhanced antioxidant defense by increasing the activities of superoxide dismutase (SOD) and catalase (CAT), as well as glutathione (GSH) levels in H2O2-exposed PC12 cells. Polymerase chain reaction (PCR) and western blot analyses revealed that tectoridin upregulated the expression of Bcl-2 while downregulating the expression of Bax, caspase-3, and caspase-9, suggesting a reduction in apoptotic signaling. In the in vivo rat model, tectoridin mitigated Aβ1-42-induced neurodegeneration, leading to improvements in spatial learning and memory performance and reduced neurofibrillary tangles. Tectoridin treatment also improved oxidative stress parameters by increasing SOD and GSH levels while reducing malondialdehyde (MDA) content. Western blot analysis further demonstrated that tectoridin downregulated the expression of amyloid-beta (Aβ1-40), amyloid precursor protein (APP), tau, Bax, caspase-3, and caspase-9, while upregulating Bcl-2. These results suggest that tectoridin exerts neuroprotective effects by modulating oxidative-antioxidant balance and inhibiting apoptotic pathways, indicating its potential as a therapeutic agent for Alzheimer's disease.},
}

Animals
*Oxidative Stress/drug effects
*Alzheimer Disease/drug therapy/metabolism/chemically induced
*Neuroprotective Agents/pharmacology/therapeutic use
Rats
*Amyloid beta-Peptides/toxicity
PC12 Cells
Male
*Hydrogen Peroxide/toxicity
Peptide Fragments/toxicity
Rats, Sprague-Dawley
Disease Models, Animal
Cell Survival/drug effects
Apoptosis/drug effects

@article {pmid40455292,
year = {2025},
author = {Liao, F and Calvo-Rodriguez, M and Chhaya, M and Sefrin, JP and Charych, EI and Mezler, M and Clausznitzer, D and McGlame, EJ and Zhao, K and Rodgers, A and Cao, Y and Secker, PF and Fernandez Garcia-Agudo, L and Huang, L and Klein, C and Dellovade, T and Karran, E},
title = {Anti-pyroglutamate-3 Aβ immunotherapy engages microglia and inhibits amyloid accumulation in transgenic mouse models of Aβ amyloidosis.},
journal = {Acta neuropathologica},
volume = {149},
number = {1},
pages = {55},
pmid = {40455292},
issn = {1432-0533},
mesh = {Animals ; Mice, Transgenic ; *Microglia/drug effects/metabolism/pathology ; Humans ; *Amyloid beta-Peptides/metabolism/immunology ; Disease Models, Animal ; *Immunotherapy/methods ; Plaque, Amyloid/pathology/metabolism ; Mice ; *Alzheimer Disease/pathology ; Brain/pathology/metabolism/drug effects ; *Amyloidosis/pathology/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; *Peptide Fragments/metabolism/immunology ; *Antibodies, Monoclonal/pharmacology ; Female ; },
abstract = {Alzheimer disease (AD) is the most common form of dementia affecting more than 6 million people in the United States. Currently, 3 monospecific antibodies targeting different Amyloid β (Aβ) species have been approved by the US FDA as disease modifying therapeutics for treatment in early AD patients with amyloid pathology. ABBV-916 is a clinical stage human IgG1 monoclonal antibody which binds to N-terminal truncated, pyroglutamate-modified at amino acid position 3, Aβ (AβpE3). The current study characterized ABBV-916 using human tissue samples and amyloid precursor protein (APP) transgenic mice. ABBV-916 selectively bound to recombinant AβpE3-42 fibrils and native amyloid plaques in unfixed AD brain tissue but did not bind targets in human CSF. ABBV-916 significantly reduced dense plaques from brain tissue that were co-cultured with hiPSC-derived phagocytes. In APPPS1-21 mice, ABBV‑916 bound plaques in a dose-dependent manner after a single intravenous injection. In addition, three months of weekly administration of ABBV-916 murine surrogate antibody significantly decreased amyloid plaques in APPPS1-21 mice. In vivo two-photon imaging revealed that the murine version of ABBV-916 inhibited the growth of the plaques in APPPS1-21 mice. ABBV-916 murine surrogate antibody recruited microglia to plaques within 24-48 hours after a single intraperitoneal injection in Cx3cr1-tdTomato/APPPS1-21 mice. Importantly, in contrast to a positive control antibody, ABBV‑916 murine precursor antibody did not cause microhemorrhage in aged APPPS1-21 mice. Taken together, our results suggest that ABBV-916 is a promising drug candidate. Clinical testing is on-going to evaluate the plaque removal and safety profiles of ABBV-916 in AD patients.},
}

Animals
Mice, Transgenic
*Microglia/drug effects/metabolism/pathology
Humans
*Amyloid beta-Peptides/metabolism/immunology
Disease Models, Animal
*Immunotherapy/methods
Plaque, Amyloid/pathology/metabolism
Mice
*Alzheimer Disease/pathology
Brain/pathology/metabolism/drug effects
*Amyloidosis/pathology/metabolism
Amyloid beta-Protein Precursor/genetics/metabolism
*Peptide Fragments/metabolism/immunology
*Antibodies, Monoclonal/pharmacology
Female

@article {pmid40454648,
year = {2025},
author = {Košak, U and Strašek Benedik, N and Knez, D and Žakelj, S and Trontelj, J and Pišlar, A and Horvat, S and Bolje, A and Žnidaršič, N and Grgurevič, N and Švara, T and Kljun, J and Skrzypczak-Wiercioch, A and Lv, B and Xiong, Y and Wang, Q and Bian, R and Shao, J and Dias, J and Nachon, F and Brazzolotto, X and Stojan, J and Sun, H and Sałat, K and Gobec, S},
title = {Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer's Disease.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c00577},
pmid = {40454648},
issn = {1520-4804},
abstract = {Butyrylcholinesterase (BChE) is a promising drug target for alleviating the symptoms of canine cognitive dysfunction (CCD) and Alzheimer's disease (AD). We have recently developed lead compound 2, a racemic, nanomolar BChE inhibitor with procognitive effects in mice with scopolamine-induced AD-like symptoms and dogs suffering from CCD. To overcome its modest brain exposure, we developed compound (R)-(-)-3, a more potent BChE inhibitor with a 7-fold higher in vivo brain exposure. It has procognitive effects in mice with scopolamine-induced AD-like symptoms and, superior to compound 2, also in mice with Aβ1-42-induced AD-like symptoms. Compound (R)-(-)-3 produces no cholinergic adverse effects or motor deficits and has no acute toxic effects in mice. This makes sulfonamide (R)-(-)-3 an optimized lead compound for alleviating the symptoms of AD.},
}

@article {pmid40454536,
year = {2025},
author = {Song, D and Zhang, C},
title = {Anti-neurodegenerative treatment in Alzheimer's disease: Multifaceted mechanisms of action of berberine.},
journal = {International journal of clinical pharmacology and therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.5414/CP204725},
pmid = {40454536},
issn = {0946-1965},
abstract = {BACKGROUND: Berberine, a traditional Chinese medicine, has demonstrated significant therapeutic influences in treating diabetes, obesity, and diarrhea, among other conditions. It has exhibited potential therapeutic benefits for various neurodegenerative diseases, namely, Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD).

AIMS: This study aims to elucidate the mechanism behind berberine pharmacological action in treating AD.

MATERIALS AND METHODS: We search the articles published in PubMed and CNKI and summarize the mechanism of berberine in AD.

RESULTS: In recent years, as research into the pharmacology of berberine has deepened, researchers have discovered its strong neuroprotective properties. The ability of berberine to enhance cognitive function is thought to result from inhibiting the spread of AD-related proteins, reducing oxidative stress and inflammation, increasing choline levels, and regulating autophagy.

CONCLUSION: This review explores the latest research on berberine in AD, suggesting that berberine and its analogs may offer a promising new approach to treating the condition.},
}

@article {pmid40454492,
year = {2025},
author = {Chauhan, BS and Singh, YP and Poeggeler, B and Singh, SK},
title = {Therapeutic Advances in Alzheimer's Disease: Integrating Natural, Semi-Synthetic, and Synthetic Drug Strategies.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050366727250513061730},
pmid = {40454492},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder associated with age, marked by progressive memory loss linked to the decline of cholinergic neurons, accumulation of amyloid plaques, and the presence of Neurofibrillary Tangles (NFTs). Neuropil threads in the brain contribute to amyloidosis and dementia. Despite extensive research, AD's etiology remains unclear, and currently, no promising therapy exists. This review examines the role of natural, semi-synthetic, and synthetic drugs in AD treatment. Natural drugs demonstrate safety and efficacy with minimal adverse effects, while most agents, whether natural or synthetic, target multiple steps or directly counteract amyloidogenesis, tau protein pathology, oxidative stress, NMDA receptor activity, inflammation, acetylcholine (AChE) function, or α, β, γ secretase activity. In pursuit of improved treatment outcomes, we explore the effectiveness and challenges of various therapeutic interventions. Our hypothesis underscores the importance of an integrated approach combining these drug types for tailored symptom relief, suggesting combined therapies may offer greater therapeutic benefits compared to single-drug approaches. The drugs discussed show potential in regulating AD, thereby presenting viable options for its management. However, to obtain more favorable results, additional studies are needed by combining these drugs.},
}

@article {pmid40454371,
year = {2025},
author = {Nadeem, M and Khan, MA and Ahmad, FJ and Parvez, S and Akhtar, M and Najmi, AK},
title = {Exploring the neuroprotective role of Asparagus racemosus (Shatavari) in Alzheimer's disease: mechanisms, evidence, and future directions.},
journal = {3 Biotech},
volume = {15},
number = {7},
pages = {197},
pmid = {40454371},
issn = {2190-572X},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disease, is characterized by cognitive decline, memory loss, and pathological features such as amyloid-beta plaques, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Current therapies do not adequately address the disease's fundamental causes, even while they provide symptomatic relief. Asparagus racemosus (Shatavari), a traditional Ayurvedic medicinal herb, has drawn interest for its neuroprotective potential in the hunt for safer and multi-targeted substitutes. It is abundant with various bioactive components, such as alkaloids, flavonoids, and steroidal saponins (shatavarins); A. racemosus has adaptogenic, anti-inflammatory, and antioxidant properties. By lowering oxidative stress, regulating neuroinflammation, and preventing the development of amyloid-beta, these may mitigate the pathophysiology of AD. In addition, preclinical research indicates that it maintains neuronal integrity, encourages neurogenesis, and increases acetylcholine levels by inhibiting cholinesterase. Moreover, via controlling the hypothalamic-pituitary-adrenal (HPA) axis, its adaptogenic actions may lessen stress-induced neurotoxicity. Preclinical evidence is encouraging, but there are still important limits. There are few human clinical trials available, and there are still unanswered questions about extract standardization, bioavailability, and long-term safety. Moreover, thorough mechanistic research is required to elucidate its therapeutic targets and interactions due to the intricacy of its phytochemical makeup. To improve effectiveness and bioavailability, future studies should focus on creating standardized formulations, including cutting-edge delivery methods like nanoformulations. To confirm its therapeutic potential and safety profile in AD patients, extensive, rigorous clinical studies are necessary. By addressing these issues, Asparagus racemosus may be positioned as a viable alternative or adjuvant in the treatment of AD.},
}

@article {pmid40454317,
year = {2025},
author = {Morimoto, T},
title = {Transcorneal electrical stimulation: impact on healthcare and future potential.},
journal = {Frontiers in cell and developmental biology},
volume = {13},
number = {},
pages = {1569759},
pmid = {40454317},
issn = {2296-634X},
abstract = {Transcorneal electrical stimulation (TES), a noninvasive therapeutic technique, has gained attention for its potential to treat retinal and optic nerve diseases. TES involves applying weak electrical currents via electrodes on the cornea to stimulate retinal ganglion cells (RGCs) without causing activation of photoreceptors, inducing phosphenes, and enabling the evaluation of inner retinal function. This is valuable for assessing residual retinal activity in patients with photoreceptor or RGC degeneration. Furthermore, TES has shown significant neuroprotective effects on RGCs and photoreceptors through mechanisms involving the upregulation of neurotrophic factors (e.g., insulin-like growth factor 1, brain-derived neurotrophic factor, and ciliary neurotrophic factor), reduction of inflammatory responses, and enhanced ocular blood flow. These findings are supported by extensive animal studies, showing its efficacy in mitigating retinal degeneration and optic nerve damage while promoting axonal regeneration. Clinically, TES has shown potential in improving visual function in diseases such as RP, optic neuropathies, and ischemic retinal conditions; however long-term benefits remain a challenge. Randomized controlled trials have indicated the safety and modest therapeutic effects of TES, suggesting its potential as an adjunct treatment for visual impairments. Moreover, TES may extend beyond ophthalmology into neurology. Because the retina is anatomically connected to the brain, TES can influence brain regions such as the visual cortex and hippocampus. Preliminary research proposes its potential for modulating brain, such as those with retinitis pigmentosa (RP). TES has demonstrated significant neuroprotective effects in networks, cognition, and emotional pathways, offering hope for treating neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In summary, TES represents a versatile and promising therapy for retinal and neurological disorders, and ongoing advancements will likely expand its applications in clinical practice. Further studies are warranted to optimize its parameters, enhance its efficacy, and explore its full therapeutic potential.},
}

@article {pmid40453977,
year = {2025},
author = {Nakashima, S and Sato, K and Niimi, Y and Ihara, R and Suzuki, K and Iwata, A and Toda, T and Iwatsubo, T and , },
title = {Therapeutic time window of disease-modifying therapy for early Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70102},
pmid = {40453977},
issn = {2352-8737},
abstract = {INTRODUCTION: Recently approved disease-modifying therapies (DMT) for early Alzheimer's disease (AD), including lecanemab and donanemab, require patients to meet specific eligibility criteria for treatment. These criteria define a limited "therapeutic time window," after which patients become ineligible as the disease advances. Understanding factors influencing this window may help clinicians optimize patient management and reduce lost treatment opportunities.

METHODS: We analyzed longitudinal data from two observational cohorts, the National Alzheimer's Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). At each visit, individuals were deemed eligible if they were amyloid-positive and had a Mini-Mental State Examination (MMSE) score of 22-30 (lecanemab) or 20-30 (donanemab), plus a Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 or 1. We then applied survival analyses and Cox proportional hazards models to estimate time-to-ineligibility based on baseline cognitive status.

RESULTS: Across both datasets, higher baseline CDR-GS and MMSE were associated with a lower risk of becoming ineligible (pooled hazard ratio of 1.601 for CDR-GS of 1 vs. 0.5, and pooled hazard ratio of 0.660 per 1-point increase in MMSE score above the lower limit of eligibility). The estimated 75% survival time for patients with baseline CDR-GS 0.5 was over 12 months, suggesting only 25% would become ineligible within 12 months. For those with CDR-GS 1, the estimated 50% survival time was approximately 12 months, depending on the data, indicating that half might become ineligible within 1 year.

DISCUSSION: We quantitatively outlined the duration of the therapeutic time window for early AD patients who qualify for lecanemab or donanemab, which is significantly influenced by baseline CDR-GS and MMSE scores. These findings will support more proactive patient management, ensuring timely evaluations and prioritization of patients at higher risk of ineligibility, particularly where DMT access is limited.

HIGHLIGHTS: We examined the "therapeutic time window" eligibility for disease-modifying therapy.Longitudinal data from National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI) were used to quantify eligibility duration.Higher Clinical Dementia Rating-Global Score (CDR-GS) or lower Mini-Mental State Examination (MMSE) at baseline were associated with shorter window length.Our results will help optimize the management of the wait time for disease-modifying therapies (DMT) treatment.},
}

@article {pmid40453709,
year = {2025},
author = {Miranda, DG and Carrouel, F and Attik, N and Araujo, GF and Dos Santos Lopes, NF and Marcucci, MC and Rodrigues, FP and Caires, GA and Vigerelli, H and Godoi, BH and Pacheco-Soares, C and Ramos, LP},
title = {Juglans regia and Pfaffia paniculata extracts: implications for periodontal disease treatment and correlation with Alzheimer's risk.},
journal = {Frontiers in cellular and infection microbiology},
volume = {15},
number = {},
pages = {1585438},
pmid = {40453709},
issn = {2235-2988},
mesh = {Animals ; Mice ; *Plant Extracts/pharmacology/chemistry ; *Periodontal Diseases/drug therapy/microbiology/complications ; *Alzheimer Disease/etiology ; *Juglans/chemistry ; RAW 264.7 Cells ; Cytokines/metabolism ; Biofilms/drug effects ; Macrophages/drug effects ; Anti-Inflammatory Agents/pharmacology ; Porphyromonas gingivalis/drug effects ; Cell Survival/drug effects ; Phytochemicals/pharmacology/analysis ; Anti-Bacterial Agents/pharmacology ; Microbial Sensitivity Tests ; },
abstract = {Periodontal disease (PD) is a significant global health concern, affecting approximately 19% of the world's population. It is one of the most prevalent diseases today, causing substantial socio-economic impacts and diminished quality of life. Recent research has also revealed a potential link between PD and Alzheimer's disease. This study investigated the antimicrobial effects of Juglans regia and Pfaffia paniculata extracts against P. endodontalis and P. gingivalis, bacteria that cause PD and are related to Alzheimer's risk. The study also assessed the impact of these extracts on macrophage metabolic activity, pro- and anti-inflammatory cytokine expression, and genotoxicity. The phytochemical analysis of the extract was carried out first. Antimicrobial activity was performed using the M11-A7 protocol (CLSI) for planktonic cultures on monotypic biofilms matured for 168 hours in anaerobiosis. Cell viability analysis was carried out using MTT on mouse macrophages (RAW 264-7), as well as genotoxicity assessment using micronuclei. The anti-inflammatory activity was evaluated using ELISA method, checking the cytokines IL-6, IL-1B, TNF-alpha, IL-17 and IL-10. Phytochemical analysis revealed the presence of Miquelianin, Regiolone and Gallic Acid in J. regia extract. For the P. paniculata extract, we identified the glycosides Pfaffoside C, Pfaffoside A, 3-O-β-D-glycopyranosyl-oleanolic acid and Beta-ecdysone. Antimicrobial activity revealed a MBC of 1.73 for the extract of J. regia and 0.48 for P. paniculata against P. endodontalis and P. gingivalis. All biofilms were reduced by more than 89% after treatment with the extracts for 5 min. Cytotoxicity evaluations revealed that cell viability remained above 50% at concentrations up to 0.216 mg/ml for J. regia and 0.015 mg/ml for P. paniculata. Neither extract exhibited genotoxicity. Furthermore, both demonstrated anti-inflammatory activity by promoting the production of the cytokine IL-10. In conclusion, the antimicrobial and anti-inflammatory activities of J. regia and P. paniculata extracts suggest their potential as treatments for oral dysbiosis, which may contribute to a reduced risk of neurodegenerative diseases.},
}

Animals
Mice
*Plant Extracts/pharmacology/chemistry
*Periodontal Diseases/drug therapy/microbiology/complications
*Alzheimer Disease/etiology
*Juglans/chemistry
RAW 264.7 Cells
Cytokines/metabolism
Biofilms/drug effects
Macrophages/drug effects
Anti-Inflammatory Agents/pharmacology
Porphyromonas gingivalis/drug effects
Cell Survival/drug effects
Phytochemicals/pharmacology/analysis
Anti-Bacterial Agents/pharmacology
Microbial Sensitivity Tests

@article {pmid40452483,
year = {2025},
author = {Stone, J},
title = {What is frustrating the search for treatment of dementia? Fraud or ideas?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251346044},
doi = {10.1177/13872877251346044},
pmid = {40452483},
issn = {1875-8908},
abstract = {The search for a treatment for dementia has been troubled by recent evidence of laboratory fraud. While acknowledging the seriousness of fraud, the author argues that the search for treatment has been slowed more by scientists' failure adequately to address two questions: 1) Why is dementia delayable before diagnosis yet unstoppable after diagnosis? And 2) How did molecular markers of dementia (like the peptide Aβ) evolve? What do they do for the individual, that made their evolution possible? These questions are addressed and their implications for the delay and treatment of dementia are discussed.},
}

@article {pmid40452368,
year = {2025},
author = {Yu, K and Jiang, R and Zhou, D and Zhao, Z},
title = {Therapeutic targets for Alzheimer's disease: Proteome-wide Mendelian randomization and colocalization analyses.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251344572},
doi = {10.1177/13872877251344572},
pmid = {40452368},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a major neurodegenerative disorder with limited treatment options.ObjectiveThis study aimed to identify novel therapeutic targets for AD using proteome-wide Mendelian randomization (MR) and colocalization analyses.MethodsWe conducted a large-scale, proteome-wide MR analysis using data from two extensive genome-wide association studies (GWASs) of plasma proteins: the UK Biobank Pharma Proteomics Project (UKB-PPP) and the deCODE Health Study. We extracted genetic instruments for plasma proteins from these studies and utilized AD summary statistics from European Bioinformatics Institute GWAS Catalog. Colocalization analysis assessed whether identified associations were due to shared causal variants. Phenome-wide association studies and drug repurposing analyses were performed to assess potential side effects and identify existing drugs targeting the identified proteins.ResultsOur MR analysis identified significant associations between genetically predicted levels of 9 proteins in the deCODE dataset and 17 proteins in the UKB-PPP dataset with AD risk after Bonferroni correction. Four proteins (BCAM, CD55, CR1, and GRN) showed consistent associations across both datasets. Colocalization analysis provided strong evidence for shared causal variants between GRN, CR1, and AD. PheWAS revealed minimal potential side effects for CR1 but suggested possible pleiotropic effects for GRN. Drug repurposing analysis identified several FDA-approved drugs targeting CR1 and GRN with potential for AD treatment.ConclusionsThis study identifies GRN and CR1 as promising therapeutic targets for AD. These findings provide new directions for AD drug development, but further research and clinical trials are warranted to validate the therapeutic potential of these targets.},
}

@article {pmid40452356,
year = {2025},
author = {Shi, Y and Tang, Y and Wang, Y and Fei, X and Xu, X and Zhang, Y},
title = {Investigating the relationship between visual impairment and cognitive impairment in the older adults using the novel vision screening assessment (VISA) tool.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251344218},
doi = {10.1177/13872877251344218},
pmid = {40452356},
issn = {1875-8908},
abstract = {BackgroundEarly identification and multimodal treatment of dementia, especially Alzheimer's disease, is a common goal of global efforts.ObjectiveThis study aims to investigate the relationship between visual impairment (VI) and cognitive impairment in older adults using the Vision Screening Assessment (VISA) tool.MethodsA total of 94 healthy older adults from community settings in Changzhou were recruited for the study. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) and the Clock Drawing Test (CDT). The VISA tool was employed to evaluate participants' visual acuity, ocular motility, visual fields, and visual attention.ResultsThis study examined 94 participants, identifying 80 with VI, 26 with abnormal visual attention, 58 with cognitive impairment, and 11 with visuospatial dysfunction. Analyses showed: (1) Visual acuity negatively correlated with MMSE and CDT scores; (2) Groups with near vision impairment or visual attention abnormalities had significantly lower MMSE and CDT scores, while cognitively normal participants showed better visual acuity; (3) Logistic regression revealed MMSE scores were primarily influenced by left-eye near vision and visual attention, whereas CDT scores were additionally affected by education level; (4) Mediation analysis indicated left-eye near vision and visual attention may impact cognitive function via visuospatial function.ConclusionsVI is closely associated with cognitive impairment, with left-eye near vision and visual attention potentially affecting cognition through their impact on visuospatial function. The application of the VISA tool may provide scientific evidence for optimizing dementia prevention and control strategies in China.},
}

@article {pmid40452353,
year = {2025},
author = {Li, L and Wang, Y and Feng, Q and Ma, C and He, C and Wan, W and Tang, L},
title = {Role of astroglia and microglia in Alzheimer's disease and multiple therapeutic interventions.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251335572},
doi = {10.1177/13872877251335572},
pmid = {40452353},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) formed by aggregates of hyperphosphorylated tau proteins. It presents a formidable global health challenge, prompting the exploration of innovative therapeutic strategies. This review aims to provide a thorough discussion of astrocytes and microglia to examine whether they are overall beneficial or detrimental for AD on the global level. Based on this, this review describes the treatment solutions that are likely to entail the manipulation of glial cells to reduce inflammation, opting to boost clearance of toxic proteins, thus stabilizing the effects of AD. These glial entities, inherent to the central nervous system, extend their functions beyond structural support, actively engaging in various physiological and pathological processes associated with AD. Both astroglia and microglia contribute significantly to the neuroinflammatory response observed in AD. Reactive astrocytes release inflammatory mediators, while activated microglia release cytokines, chemokines, and reactive oxygen species, collectively assisting a chronic state of neuroinflammation. Additionally, astrocytes partake in the clearance of Aβ, while microglia play a pivotal role in phagocytosing Aβ plaques. In AD, ongoing inflammation may cause a buildup of Aβ, which causes problems with the functions of astroglia and microglia and also worsens these issues with communication between neurons, a key factor in cognitive decline. In addition, there are tremendous opportunities to identify new biomarkers specific to glial disorders, genomic and epigenomic approaches for the selection of patients, using multimodal imaging techniques, and the application of machine learning algorithms in the future for personalized glial-targeted therapies.},
}

@article {pmid40451789,
year = {2025},
author = {Yue, X and Yang, J and Qi, J and Gao, S and Huo, Q and Guo, X and Guo, H and Luo, J and Wang, Y and Zhao, Y and Liu, R and Wang, H and Yi, S and Fu, Y and Ji, X and Wei, Y and He, W and Guo, B},
title = {Loss of Pathogenicity and Evidence of Horizontal Gene Transfer in Colletotrichum gloeosporioides From a Medicinal Plant.},
journal = {Molecular plant pathology},
volume = {26},
number = {6},
pages = {e70098},
doi = {10.1111/mpp.70098},
pmid = {40451789},
issn = {1364-3703},
support = {GX2346//Xi'an Beilin District Science and Technology Plan Project/ ; 2018ZDXM-SF-016//Key Research and Development Plan Project of Shaanxi Province/ ; 23JHQ056//Shaanxi Institute of Basic Sciences Project/ ; 2023-JC-YB-165//Natural Science Basis Research Plan in Shaanxi Province of China/ ; },
mesh = {*Colletotrichum/pathogenicity/genetics ; *Gene Transfer, Horizontal/genetics ; *Plants, Medicinal/microbiology ; Phylogeny ; *Huperzia/microbiology ; Virulence/genetics ; },
abstract = {Colletotrichum gloeosporioides is a major agricultural pathogen of crops that has also been identified as an endophyte of the medicinal plant Huperzia serrata. Both H. serrata and C. gloeosporioides produce huperzine A, a potential treatment for Alzheimer's disease. In this study, a nonpathogenic C. gloeosporioides strain (NWUHS001) was isolated and its genome sequenced. Gene structure prediction identified 15,413 protein-coding genes and 879 noncoding RNAs. Through PHI-base database prediction, we found that NWUHS001 lacks two key pathogenicity genes CgDN3 and cap20, which may be the cause of its nonpathogenicity. Comparative genomic analysis showed that the number of genes encoding pectin lyase B (pelB), pectin lyase (pnl) and polygalacturonase (pg) in NWUHS001 was significantly lower than that in pathogenic strains during the expansion of mycelium into host tissues. This caused slow growth and incapability to penetrate host cells. In contrast, in NWUHS001, genes involved in carbon acquisition such as ribose and amino sugar metabolic pathways were enriched, indicating active metabolite exchange with the host. In addition, by comparing the genome of NWUHS001 with that of the host H. serrata, we found that polyketosynthetase (pksIII), a key gene in the host huperzine A biosynthetic pathway, may possibly have been acquired from the fungus by horizontal gene transfer (HGT). This study explained the possible genetic evolution mechanism of C. gloeosporioides from pathogenicity to nonpathogenicity, which is of value for studying the interaction between microorganisms and plants. It also provided clues to the genetic evolution of the biosynthetic pathway of huperzine A.},
}

*Colletotrichum/pathogenicity/genetics
*Gene Transfer, Horizontal/genetics
*Plants, Medicinal/microbiology
Phylogeny
*Huperzia/microbiology
Virulence/genetics

@article {pmid40450660,
year = {2025},
author = {Mumtaz, and Unnithan, D and Khan, A and Chauhan, APS and Ali, J and Khan, MA},
title = {Targeting Alzheimer's disease pathology: influence of nano-based drug delivery systems loaded with a combination of herbal and synthetic drugs.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.1080/17425247.2025.2513440},
pmid = {40450660},
issn = {1744-7593},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a progressive neurological disordermarked by cognitive decline and memory loss. Current treatments,including acetylcholinesterase inhibitors (AChEIs) and NMDA receptorantagonists, provide only symptomatic relief due to poor Blood BrainBarrier (BBB) permeability and side effects. The integration ofsynthetic and natural drug combinations with nanotechnology offers apromising strategy to enhance drug delivery, efficacy, and overalltherapeutic outcomes.

AREASCOVERED: This review explores the integration of herbal and synthetic drugs innano-based delivery systems for AD treatment. It examines co-loadingefficiency, release kinetics, and synergistic therapeutic benefits ofdual-drug formulations. Additionally, it discusses target-specificligand functionalization for improved BBB penetration and neuronaltargeting, alongside a comparative analysis of dual- vs. single-drugformulations and their impact on diseaseprogression and efficacy.

EXPERTOPINION: Current treatment options primarily offer symptomatic relief in theirearly stages, while failing to target the multiple neurobiologicalmechanisms responsible for AD progression. In light of this,combining the already established treatments with herbal drugs, wecan leverage their combined effects to enhance treatment efficacy andmitigate side effects. Furthermore, co-loading of synthetic drugs andphytoconstituents within a single nanoformulation can improvesite-specific drug delivery, offer sustained release, and lowersystemic side effects, resulting in better treatment outcomes.},
}

@article {pmid40450507,
year = {2025},
author = {Kline-Schoder, AR and Tsitsos, FN and Batts, AJ and DiBenedetto, MR and Liu, K and Bae, S and Konofagou, EE},
title = {Response of Serum-Isolated Extracellular Vesicles to Focused Ultrasound-Mediated Blood-Brain Barrier Opening.},
journal = {Ultrasound in medicine & biology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ultrasmedbio.2025.04.019},
pmid = {40450507},
issn = {1879-291X},
abstract = {OBJECTIVE: To characterize the response of extracellular vesicles (EV) in the serum of mice and Alzheimer's disease (AD) patients following focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening (FUS-BBBO) as a means to improve liquid biopsy.

METHODS: Blood was collected from C57BL/6 mice before, and one hour after FUS-BBBO, and from AD patients before, one hour after, and three days after FUS-BBBO. EVs were isolated from serum using the Exoquick precipitation solution and their concentration was quantified using nanoparticle tracking analysis. The transcriptomic and proteomic content of EVs from mice was assessed using RNA sequencing and mass spectrometry protein analysis respectively. Additionally, the release of EVs in mice was inhibited using the GW4869 drug to assess the role of EVs in the restoration of the BBB. Finally, the biomarker content of EVs in AD patients was detected using a Luminex multiplex assay.

RESULTS: We observed a 164±85% (95% confidence interval: 78.998 - 249.202) increase in murine EV concentration one hour after treatment, as well as an increase in EV RNA associated with FUS-BBBO neuroimmunotherapy. Inhibition of EVs reduced the inflammatory response and BBBO volume in mice. Patient EV concentration also increased one hour after treatment and was dependent on the volume of BBB opening three days post-treatment. Furthermore, EV isolation was found to significantly enhance (p<0.05) the detection of FUS-BBBO-induced amplification of AD and CNS biomarkers such as GFAP, beta-amyloid 42 and phosphorylated tau 181, exhibiting on average a 1.2 times higher log-fold change in biomarker levels in isolated EVs compared to total serum.

CONCLUSION: Overall, we hereby present the first evidence of altered murine and AD patient EV concentration and content in response to FUS-BBBO, providing evidence of EVs' role within FUS-BBBO neuroimmunotherapy as well as their utility in improving FUS-BBBO biomarker amplification. Our results pave the way for clinical applications of EV-based liquid biopsy in patients with neurodegenerative diseases following FUS-BBBO, as a way of noninvasively monitoring disease progression.},
}

@article {pmid40450458,
year = {2025},
author = {Bellver-Sanchis, A and Ribalta-Vilella, M and Lillo, J and Ortuño-Sahagún, D and Franco, R and Pallàs, M and Navarro, G and Griñán-Ferré, C},
title = {Neuroprotective effects of G9a inhibition and cannabinoid receptor activation in Alzheimer's disease through a pharmacological approach.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00616},
doi = {10.1016/j.neurot.2025.e00616},
pmid = {40450458},
issn = {1878-7479},
abstract = {Epigenetic alterations are key contributors to Alzheimer's disease (AD), driving age-related cognitive decline. This study explores the combined neuroprotective effects of G9a histone methyltransferase inhibition (via UNC0642) and cannabinoid receptor activation (CB1R: ACEA; CB2R: JWH133) in AD models. We used HEK-293T cells and hippocampal neurons to demonstrate that G9a inhibition selectively enhances CB1R-mediated ERK/cAMP signaling. In SAMP8 mice (sporadic AD model), we evaluated the effects of pharmacological inhibition of G9a (UNC0642), combined with CB1R agonism (ACEA) and/or CB2R agonism (JWH133), on cognitive recovery, neuronal morphology, and neuroinflammation. Our results demonstrated that SAMP8 mice treated with UNC0642 and ACEA exhibited significant recovery in short-term memory, as assessed by the Novel Object Recognition Test (NORT), and complete recovery of spatial memory in the Object Location Test (OLT). These improvements were accompanied by enhanced neuronal morphology (increased dendritic length and density) and reduced neuroinflammation markers, suggesting a synergistic effect of G9a inhibition and CB1R activation. Importantly, JWH133 treatment, both alone and in combination with UNC0642, resulted in a pronounced reduction of neuroinflammatory markers (Trem2, Cd33, iNOS) and a significant restoration of dendritic spine density and branching length, with the dual treatment showing the most robust effects. JWH133 alone produced moderate cognitive improvement, but its combination with G9a inhibition led to outcomes comparable to those of control animals. Thus, the results underscore G9a inhibition's potential to amplify cannabinoid receptor-mediated neuroprotection while mitigating psychoactive risks, offering a promising multi-target approach for neurodegenerative diseases.},
}

@article {pmid40450332,
year = {2025},
author = {Li, X and Wu, Z and Si, X and Li, J and Wu, G and Wang, M},
title = {The role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease and future strategies for targeted therapy.},
journal = {European journal of medical research},
volume = {30},
number = {1},
pages = {434},
pmid = {40450332},
issn = {2047-783X},
support = {22JR5RA994//Natural Science Foundation of Gansu Province, China/ ; 23JRRA0961//Natural Science Foundation of Gansu Province, China/ ; CY2022-MS-A07//Cuiying Scientific and Technological Innovation Program of The Second Hospital & Clinical Medical School, Lanzhou University, China/ ; CY2022-MS-A07//Cuiying Scientific and Technological Innovation Program of The Second Hospital & Clinical Medical School, Lanzhou University, China/ ; CYXZ2023-46//Cuiying Scientific Training Program for Undergraduates of The Second Hospital & Clinical Medical School, Lanzhou University, China/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/drug therapy/etiology ; *Mitochondria/pathology/metabolism ; Animals ; Molecular Targeted Therapy ; Mitochondrial Dynamics ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, behavioral impairments, and psychiatric comorbidities. The pathogenesis of AD remains incompletely elucidated, despite advances in dominant hypotheses such as the β-amyloid (Aβ) cascade, tauopathy, cholinergic deficiency, and neuroinflammation mechanisms. However, these hypotheses inadequately explain the multifactorial nature of AD, which exposes limitations in our understanding of its mechanisms. Mitochondrial dysfunction is known to play a pivotal role in AD, and since patients exhibit intracellular mitochondrial dysfunction and structural changes in the brain at an early stage, correcting the imbalance of mitochondrial homeostasis and the cytopathological changes caused by it may be a potential target for early treatment of AD. Mitochondrial structural abnormalities accelerate AD pathogenesis. For instance, structural and functional alterations in the mitochondria-associated endoplasmic reticulum membrane (MAM) can disrupt intracellular Ca[2][+] homeostasis and cholesterol metabolism, consequently promoting Aβ accumulation. In addition, the overaccumulation of Aβ and hyperphosphorylated tau proteins can further damage neurons by disrupting mitochondrial integrity and mitophagy, thereby amplifying pathological aggregation and exacerbating neurodegeneration in AD. Furthermore, Aβ deposition and abnormal tau proteins can disrupt mitochondrial dynamics through dysregulation of fission/fusion proteins, leading to excessive mitochondrial fragmentation and subsequent dysfunction. Additionally, hyperphosphorylated tau proteins can impair mitochondrial transport, resulting in axonal dysfunction in AD. This article reviews the biological significance of mitochondrial structural morphology, dynamics, and mitochondrial DNA (mtDNA) instability in AD pathology, emphasizing mitophagy abnormalities as a critical contributor to AD progression. Additionally, mitochondrial biogenesis and proteostasis are critical for maintaining mitochondrial function and integrity. Impairments in these processes have been implicated in the progression of AD, further highlighting the multifaceted role of mitochondrial dysfunction in neurodegeneration. It further discusses the therapeutic potential of mitochondria-targeted strategies for AD drug development.},
}

Humans
*Alzheimer Disease/pathology/metabolism/drug therapy/etiology
*Mitochondria/pathology/metabolism
Animals
Molecular Targeted Therapy
Mitochondrial Dynamics
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid40448955,
year = {2025},
author = {Jiang, J and Xing, Y and Liu, S and Na, Y and Lei, X and Geng, F and Zhang, Y and Yang, L and Zhang, N},
title = {Angiopep-2 modified naringin nanoparticles for Alzheimer's disease therapy overcoming BBB.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/1061186X.2025.2514575},
pmid = {40448955},
issn = {1029-2330},
abstract = {Naringin (4',5,7-trihydroxyflavanone-7-rhamnoglucoside, NG), a potential treatment for Alzheimer's disease (AD), has strong neuroprotective effects but is limited by poor solubility, low bioavailability, and limited brain accumulation. To address these issues, we developed ANG-NG-NPs, a novel NG-loaded poly (ethylene glycol)-poly(ε-caprolactone) copolymers (PEG-PCL) nanoparticle modified with the brain-targeting peptide Angiopep-2 (TFFYGGSRGKRNNFKTEEY, ANG). ANG-NG-NPs exhibited an average size of 126.1 ± 4.50 nm, a zeta potential of -2.97 ± 0.29 mV, 73.43% ± 0.80% encapsulation efficiency (EE), and 24.68% ± 0.45% drug loading capacity (LC). In vitro release studies confirmed its sustained-release properties. In vivo, ANG-NG-NPs extended NG's circulation time and increased brain uptake. Notably, ANG-NG-NPs restored learning and memory in APP/PS1 mice, improved hippocampal cell health, and reduced hyperphosphorylated tau protein (p-Tau) expression. These findings suggest ANG-NG-NPs as a promising brain-targeting system for treating central nervous system disorders.},
}

@article {pmid40448884,
year = {2025},
author = {Azizzadeh, A and Najafi, M and Nafar, Z and Salehzehi, S and Azadikhah Jahromi, S and Fallah, H and Ghoshouni, H and , },
title = {Postmortem neuropathologies are associated with retrospective tensor-based morphometry findings in Alzheimer's dementia continuum.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40448884},
issn = {1590-3478},
abstract = {BACKGROUND: Understanding the relationship between postmortem neuropathological findings and in vivo imaging biomarkers is crucial for advancing the early diagnosis and treatment of Alzheimer's disease (AD). This study investigates the association between postmortem neuropathologies and retrospective Tensor-Based Morphometry (TBM) findings across the Alzheimer's dementia continuum.

METHODS: This study utilized tensor-based morphometry (TBM) to investigate structural brain changes associated with AD neuropathology. Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed, including MRI scans and neuropathological findings from 98 participants. Logistic regression was used to explore the relationship between TBM indices and neuropathological outcomes. The diagnostic performance of TBM was evaluated using accuracy analysis.

RESULTS: Significant differences in TBM indices (StatROI and TempROI) were observed between the dementia and non-dementia groups. Logistic regression indicated that higher StatROI and TempROI indices were associated with lower odds of AD pathology, such as amyloid plaques (OR = 0.939 and 0.927), neurofibrillary tangles (OR = 0.961 and 0.931), and neuritic plaques (OR = 0.943 and 0.916). Accuracy analysis demonstrated good discriminatory power of TBM indices in differentiating pathologically confirmed AD from non-AD dementia (sensitivity up to 61.29, specificity up to 93.33%) and cognitively normal individual (sensitivity up to 82.26, specificity up to 75%).

CONCLUSION: TBM is a promising tool for predicting the underlying neuropathology of AD and distinguishing between different causes of dementia. Integrating TBM into clinical assessments can enhance the accuracy of AD diagnosis and improve patient management.},
}

@article {pmid40448828,
year = {2025},
author = {Chamorro, LB and Zulli, B and Barone, E},
title = {Insulin resistance: fueling oxidative stress and neurodegeneration.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {40448828},
issn = {1435-1463},
support = {RM120172A3160B53//Sapienza Università di Roma/ ; RG11916B87F55459//Sapienza Università di Roma/ ; 1130944/22//Banca d'Italia/ ; 2019-AARG-643091/ALZ/Alzheimer's Association/United States ; },
abstract = {The growing prevalence of age-related neurodegenerative diseases is a consequence of population aging and demands urgent treatment strategies. This literature review aims to provide a comprehensive overview of the contribution of oxidative stress and insulin resistance in neurodegenerative diseases, specifically Alzheimer's disease (AD). In addition, current therapeutic approaches to treat oxidative stress and insulin resistance in this age-related neurodegenerative disease will be discussed. AD is the most prevalent form of neurodegenerative disease and is marked at early stages by oxidative stress and insulin resistance. Results indicate that insulin resistance may be central in generating oxidative stress and exacerbating AD hallmarks. In turn, insulin resistance can be influenced by other factors, including amyloid beta (Aβ), impaired biliverdin-reductase A (BVR-A) activity, and the gut microbiota. Defective insulin signaling in the brain comes with consequences ranging from declined cognitive functions, impaired autophagy, mitochondrial dysfunction, hyperphosphorylation of Tau, and increased Aβ production. Multiple therapeutic approaches that target oxidative stress or brain insulin resistance, such as antioxidant supplementation and anti-diabetic drugs, have mostly been inconclusive, except for intranasal insulin. Positive results have been obtained in clinical trials using nasal delivery devices to administer insulin; however, results are inconsistent across studies likely due to inconsistencies in the delivery method. Future investigations should focus on investigating the molecular link between oxidative stress, insulin resistance, and AD to address current knowledge gaps. Moreover, more focus should be given to optimizing the reliability and efficacy of nasal delivery devices before considering such an approach viable to treat neurodegenerative diseases.},
}

@article {pmid40448817,
year = {2025},
author = {Goel, F},
title = {Exploring the therapeutic role of Moringa oleifera in neurodegeneration: antioxidant, anti-inflammatory, and neuroprotective mechanisms.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40448817},
issn = {1568-5608},
abstract = {Neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and other cognitive impairment conditions in elderly are defined by progressive loss of neurons, based mostly on oxidative stress, long-term neuroinflammation, and compromised neuroplasticity. In the midst of increasing investigation for natural drugs, Moringa oleifera, a plant highly accepted for its high nutritional and phytochemical constitution, has become an active candidate with multi-oriented neuroprotective activity. This review discusses the therapeutic potential of Moringa oleifera in neurodegeneration, based on its antioxidant, anti-inflammatory, and neuroprotective activities. The plant's bioactive molecules, flavonoids, phenolic acids, and vitamins exhibit potent free radical-scavenging activity and the ability to modulate crucial inflammatory signaling pathways, like NF-κB and MAPK signaling. Additionally, Moringa oleifera is shown to possess the potential for enhancing neurogenesis, facilitating synaptic plasticity, and neuronal apoptosis protection. Preclinical evidence supports its efficacy in decreasing neuropathological alterations and enhancing cognitive function, whereas initial clinical data suggest a benign safety profile. In spite of these promising observations, additional work is required to confirm its action in human subjects and to standardize therapeutic regimens. This review highlights the promise of Moringa oleifera as an adjunct treatment for the prevention and management of neurodegenerative disorders and points to avenues for future investigation and clinical utility.},
}

@article {pmid40448810,
year = {2025},
author = {Zavala, E and Zimmerman, T},
title = {Alexander's Disease: Potential Drug Targets and Future Directions.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40448810},
issn = {1559-1182},
abstract = {Alexander's disease is a rare neurodegenerative disorder primarily characterized by upregulation of the GFAP gene and the formation of Rosenthal fibers. Its prognosis is fatal, with limited treatment options currently available. The GFAP protein is a marker for mature astrocytes. It results in the upregulation of reactive astroglioses. Reactive astroglioses is a neuroprotective condition that, when functioning correctly, helps protect the brain from stress and injury and prevents further injury. However, unregulated reactive astroglioses is linked with many neurodegenerative diseases. Due to the relative rarity in the incidence of AxD, treatment options have not been as widely investigated. This review explores potential drug targets that may impact GFAP gene expression, such as STAT3, GDNF, NF-kB, LCN-2, and the LPS pathway. These drug targets have previously been or are currently being explored in other neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. The only treatment option currently in clinical trial phases involves methods to induce the knockout of the GFAP gene. Due to GFAP's neuroprotective role in brain injury and stress, it is important to explore alternative treatment options that downregulate GFAP as opposed to shutting it off entirely.},
}

@article {pmid40448625,
year = {2025},
author = {Qin, F and Cao, R and Bai, X and Yuan, J and Sun, W and Zheng, Y and Qi, X and Zhao, W and Liu, B and Gao, C},
title = {Listerin Alleviates Alzheimer's Disease through IRE1-mediated Decay of TLR4 mRNA.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e14956},
doi = {10.1002/advs.202414956},
pmid = {40448625},
issn = {2198-3844},
support = {82222027//National Natural Science Foundation of China/ ; 32270918//National Natural Science Foundation of China/ ; 82321002//National Natural Science Foundation of China/ ; 32230033//National Natural Science Foundation of China/ ; 2024YFA0918401//National key research and development program/ ; 2023YFC2306102//National key research and development program/ ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, accounting for ≈60-70% of all dementia cases worldwide. Microglial-mediated brain inflammation is thought to play key roles in AD progression. Clinical evidence and animal models have indicated that the ribosome-associated quality control (RQC) component Listerin is involved in the development of AD. How Listerin regulates the development and progression of AD is unknown. Here, it is demonstrated that Listerin can decrease brain inflammation and alleviate AD-related cognitive impairments. Microglial-specific knockout of Listerin exhibits deteriorative cognitive symptoms based on the extracellular Amyloid-β (Aβ) or Lipopolysaccharide (LPS) injection. Mechanistically, Listerin directly binds to Toll-like receptor 4 (TLR4) mRNA and facilitates the IRE1α-mediated cleavage and degradation of TLR4 mRNA, leading to the alleviation of TLR4-induced brain inflammation. Adenovirus-mediated overexpression of Listerin decelerates the disease progression in the mouse model of Aβ-mediated neurodegeneration. Thus, Listerin is an important suppressor of microglia-induced brain inflammation and may be a potential therapeutic target for AD treatment.},
}

@article {pmid40448382,
year = {2025},
author = {Tang, H and Donahoo, WT and DeKosky, ST and Lee, YA and Kotecha, P and Svensson, M and Bian, J and Guo, J},
title = {Heterogeneous treatment effects of GLP-1RAs and SGLT2is on risk of Alzheimer's disease and related dementia in patients with type 2 diabetes: Insights from a real-world target trial emulation.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70313},
doi = {10.1002/alz.70313},
pmid = {40448382},
issn = {1552-5279},
support = {2023PDVH1064032//The Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation Predoctoral Fellowship/ ; R01AG089445//National Institutes of Health (NIH)/National Institute on Aging (NIA)/ ; R01AG076234//National Institutes of Health (NIH)/National Institute on Aging (NIA)/ ; R01DK133465//NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/complications ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; *Alzheimer Disease/epidemiology/prevention & control ; Male ; Female ; Aged ; *Glucagon-Like Peptide-1 Receptor Agonists ; Middle Aged ; *Hypoglycemic Agents/therapeutic use ; *Dementia/epidemiology/prevention & control ; Risk Factors ; Treatment Effect Heterogeneity ; },
abstract = {INTRODUCTION: This study assessed the heterogeneous treatment effects (HTEs) of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) on the risk of Alzheimer's disease and related dementias (ADRD).

METHODS: This target trial emulation study included adults (≥ 50 years) with type 2 diabetes (T2D) and newly prescribed a GLP-1RA, SGLT2i, or other second-line glucose-lowering drugs (GLDs). A doubly robust learning approach was deployed to estimate the risk difference (RD) of ADRD and identify key subgroups.

RESULTS: Both GLP-1RAs (RD, -1.5%) and SGLT2is (-1.7%) were associated with a reduced ADRD risk compared to other GLDs. Key subgroups were determined based on cardiovascular disease (CVD), cerebrovascular disease (CeVD), chronic kidney disease, and Hispanic ethnicity. Patients with CVD and CeVD had the greatest benefits from GLP-1RAs (-4.8%) and SGLT2is (-4.6%). No overall difference was observed between GLP-1RAs and SGLT2i.

DISCUSSION: These findings suggest the importance of personalized treatment in diabetes management regarding ADRD risk.

HIGHLIGHTS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were associated with a decreased risk of Alzheimer's disease and related dementias (ADRD), while the protective association varied across subgroups defined by cardiovascular disease (CVD), cerebrovascular disease (CeVD), and chronic kidney disease (CKD). Similarly, sodium-glucose cotransporter-2 inhibitors (SGLT2is) were associated with a decreased risk of ADRD, with the protective association varying among subgroups defined by CVD, CeVD, and Hispanic ethnicity. There was no difference between GLP-1RAs and SGLT2is in the risk of ADRD.},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy/complications
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
*Alzheimer Disease/epidemiology/prevention & control
Male
Female
Aged
*Glucagon-Like Peptide-1 Receptor Agonists
Middle Aged
*Hypoglycemic Agents/therapeutic use
*Dementia/epidemiology/prevention & control
Risk Factors
Treatment Effect Heterogeneity

@article {pmid40447541,
year = {2025},
author = {Thientunyakit, T and Muangpaisan, W and Minoshima, S},
title = {[18]F-FDG PET for Dementia Evaluation: Co-pathologies, New Diseases, and Its Roles in the Era of Antiamyloid Treatment.},
journal = {Seminars in nuclear medicine},
volume = {},
number = {},
pages = {},
doi = {10.1053/j.semnuclmed.2025.04.007},
pmid = {40447541},
issn = {1558-4623},
abstract = {Dementia, which impairs a person's cognition and ability in daily tasks and is often caused by neurodegenerative disorders, remains one of the most challenging neuropsychiatric conditions. The prevalence of dementia has been steadily increasing in aging societies. Recently, antiamyloid treatment has been developed and approved for the treatment of Alzheimer's disease (AD), which is known as the major cause of dementia. Such therapeutic developments have accelerated the use of in vivo biomarkers in research, clinical trials, and clinical practice. Past and recent developments of several biomarkers, including [18]F-fluorodeoxyglucose (FDG) positron emission tomography (PET), have played a pivotal role in understanding the underlying mechanisms of dementing disorders and accelerating progress in both research and clinical practice, leading to more accurate clinical diagnosis, recognition of co-pathologies, better understanding of new diseases, treatment planning, and response evaluation. This article reviews the roles of brain FDG PET, one of the well-established imaging biomarkers, as a valuable tool for studying brain metabolism and its applications in clinical and research settings, particularly for the treatment of dementia.},
}

@article {pmid40445951,
year = {2025},
author = {Li, B and Jiang, X and Zhang, K and Harmanci, AO and Malin, B and Gao, H and Shi, X and , },
title = {Enhancing fairness in disease prediction by optimizing multiple domain adversarial networks.},
journal = {PLOS digital health},
volume = {4},
number = {5},
pages = {e0000830},
pmid = {40445951},
issn = {2767-3170},
abstract = {Predictive models in biomedicine need to ensure equitable and reliable outcomes for the populations they are applied to. However, biases in AI models for medical predictions can lead to unfair treatment and widening disparities, underscoring the need for effective techniques to address these issues. However, current approaches struggle to simultaneously mitigate biases induced by multiple sensitive features in biomedical data. To enhance fairness, we introduce a framework based on a Multiple Domain Adversarial Neural Network (MDANN), which incorporates multiple adversarial components. In an MDANN, an adversarial module is applied to learn a fair pattern by negative gradients back-propagating across multiple sensitive features (i.e., the characteristics of patients that should not lead to a prediction outcome that may intentionally or unintentionally lead to disparities in clinical decisions). The MDANN applies loss functions based on the Area Under the Receiver Operating Characteristic Curve (AUC) to address the class imbalance, promoting equitable classification performance for minority groups (e.g., a subset of the population that is underrepresented or disadvantaged.) Moreover, we utilize pre-trained convolutional autoencoders (CAEs) to extract deep representations of data, aiming to enhance prediction accuracy and fairness. Combining these mechanisms, we mitigate multiple biases and disparities to provide reliable and equitable disease prediction. We empirically demonstrate that the MDANN approach leads to better accuracy and fairness in predicting disease progression using brain imaging data and mitigating multiple demographic biases for Alzheimer's Disease and Autism populations than other adversarial networks.},
}

@article {pmid40445481,
year = {2025},
author = {Eciroglu-Sarban, H and Altin-Celik, P and Kelicen-Ugur, P and Donmez-Altuntas, H},
title = {Neuroprotective Effects of Hesperidin and CK2 Inhibitor DRB on Aβ1-42-Induced Neurotoxicity in Differentiated SH-SY5Y Cells.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40445481},
issn = {1559-1182},
support = {TDK-2020-10151//Bilimsel Araştırma Projeleri, Erciyes Üniversitesi/ ; TDK-2020-10151//Bilimsel Araştırma Projeleri, Erciyes Üniversitesi/ ; },
abstract = {There is still no approved treatment for Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid plaques, neurofibrillary tangles, and synaptic dysfunction. In an in vitro AD model, this study aimed to comparatively assess the neuroprotective effects of the citrus flavonoid Hesperidin and the casein kinase 2 (CK2) inhibitor 5,6-dichloro-1-β-D-ribofuranosyl benzimidazole (DRB) as potential therapeutic targets for AD. First, SH-SY5Y neuroblastoma cells were differentiated into cholinergic neuron-like cells using all-trans retinoic acid (RA) and brain-derived neurotrophic factor (BDNF). Then, to generate an in vitro AD model, 20 μM Aβ1-42 was applied to induce neurotoxicity in differentiated SH-SY5Y cells. The neuroprotective effects of the CK2 inhibitor DRB and Hesperidin on the in vitro AD model were evaluated using MTT, RT-qPCR, and ELISA methods. Both Hesperidin and DRB, at high concentrations, reduced cell viability in differentiated SH-SY5Y cells for 24 and 48 h (p < 0.05 to p < 0.01). Pre-treatment with Hesperidin at 25 and 50 µM and DRB at 0.25 and 0.5 µM for 24 h increased ADAM10 gene expression and decreased BACE1 gene expression, both of which are associated with AD markers, compared to the 20 µM Aβ1-42 treatment group (p < 0.05). Pre-treatment with the DRB at 0.25 and 0.5 µM concentrations for 24 h decreased CK2α gene expression in the in vitro AD model compared to the 20 µM Aβ1-42 treatment group (p < 0.05), whereas Hesperidin had no effect (p > 0.05). Both pre-treatment with Hesperidin and DRB significantly decreased Aβ1-42 levels (p < 0.01), p-Tau (T181) levels (p < 0.05), and the Bax/Bcl-2 ratio (p < 0.05). As a result, our study showed that both Hesperidin and DRB inhibited Aβ production by suppressing the amyloidogenic pathway and activating the non-amyloidogenic pathway while also exerting an inhibitory effect on neuronal apoptosis. CK2 may be a potential therapeutic target and could contribute to the pathophysiology of AD. However, these findings should be validated by further studies.},
}

@article {pmid40380353,
year = {2025},
author = {Andersohn, F and Christensen, MC and Creuwels, L and Aznar-Lou, I and Rubio-Valera, M and Penning-van Beest, F and Houben, E and Hernandez, P and Hakkarainen, KM and Reines, EH},
title = {Vortioxetine in the routine management of major depressive disorder: an analysis of European automated healthcare databases.},
journal = {Current medical research and opinion},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/03007995.2025.2505692},
pmid = {40380353},
issn = {1473-4877},
abstract = {OBJECTIVE: Vortioxetine is a multimodal antidepressant approved for the treatment of major depressive episodes. As part of the overall European risk-management plan, we aimed to fill data gaps on relevant missing information such as the extent of vortioxetine use in special populations and assessment of selected potential risks.

METHODS: This non-interventional post-authorization safety study used longitudinal administrative claims/medical records data from 10,358 patients newly prescribed vortioxetine in Finland, Spain, and the Netherlands (EU-PAS register: EUPAS19199).

RESULTS: Elderly patients (≥75 years) accounted for 3-14% of the assessed populations, while off-label pediatric prescribing was low (0.1-0.5%). Patients with a comorbid diagnosis of mania/hypomania accounted for 0.4-10% of the population, while patients with comorbid neurological conditions accounted for ≤3% of patients. The median prescribed daily vortioxetine dose was 10 mg and mean exposure was 72-238 days. The proportions of patients who had one of the events of interest (suicidal events, epilepsy, convulsions/seizures, severe renal or hepatic events) recorded during vortioxetine exposure were all ≤1%.

CONCLUSION: In this European healthcare database study, the extent and characteristics of vortioxetine use were in line with clinical trial experience and the current label. Analyses of events, including those of special interest, did not raise any new safety concerns.},
}

@article {pmid40445426,
year = {2025},
author = {Lv, X and Ye, T and Yang, W and Zhu, Z and Xiang, K and Zhan, L and Sun, J and Liu, J},
title = {Weissella confusa Attenuates Cognitive Deficits in Alzheimer's Disease by Reducing Oxidative Stress Via the SIRT1/PGC-1α Signaling Pathway.},
journal = {Neurochemical research},
volume = {50},
number = {3},
pages = {175},
pmid = {40445426},
issn = {1573-6903},
support = {LY23H250001//Natural Science Foundation of Zhejiang Province/ ; },
mesh = {*Oxidative Stress/drug effects/physiology ; Animals ; *Sirtuin 1/metabolism ; *Alzheimer Disease/metabolism/drug therapy ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Signal Transduction/drug effects/physiology ; Mice ; Mice, Transgenic ; *Cognitive Dysfunction/metabolism ; Male ; *Probiotics/therapeutic use/pharmacology ; Mitochondria/metabolism/drug effects ; Humans ; Mice, Inbred C57BL ; },
abstract = {Emerging evidence suggests that probiotics may have a significant impact on the regulation of mitochondrial oxidative stress in Alzheimer's disease (AD). However, the research focusing on the specific bacteria responsible for mitochondrial oxidative stress of AD remains limited. This study explores the impact and underlying mechanisms of probiotic W. confusa WMU005 on mitochondrial oxidative stress in AD. The probiotic W. confusa WMU005 was isolated from the healthy people. APP/PS1 mice were administered live W. confusa WMU005 for 4 weeks and then subjected to cognitive test. Aβ deposition, Tau phosphorylation, neuronal apoptosis, oxidative stress, and mitochondrial damage of brain were measured. Additionally, APP/SWE cells treated with W. confusa WMU005 fermentation broth showed altered levels of silent information regulator 1 (SIRT1) and proliferator-activated receptor γ coactivator 1α (PGC-1α). Meanwhile, we confirmed that W. confusa WMU005 could regulate SIRT1 pathway in APP/PS1 mice. Our results revealed that W. confusa WMU005 improved cognitive function, reduced Aβ and Tau pathology. Furthermore, W. confusa WMU005 treatment exerted antioxidative effects by activating the SIRT1 pathway. We further demonstrated that W. confusa WMU005 mitigated the mitochondrial oxidative stress via activating SIRT1 pathway in vitro. Meanwhile, we revealed that W. confusa WMU005 effectively inhibited the mitochondrial oxidative stress in the APP/PS1 mice by regulating SIRT1 pathway. These findings suggest that W. confusa WMU005 exerts protective effects on AD through the involvement of the SIRT1 signaling pathway, which opened avenues for novel therapeutic strategies towards treating AD.},
}

*Oxidative Stress/drug effects/physiology
Animals
*Sirtuin 1/metabolism
*Alzheimer Disease/metabolism/drug therapy
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
Signal Transduction/drug effects/physiology
Mice
Mice, Transgenic
*Cognitive Dysfunction/metabolism
Male
*Probiotics/therapeutic use/pharmacology
Mitochondria/metabolism/drug effects
Humans
Mice, Inbred C57BL

@article {pmid40445128,
year = {2025},
author = {Gharai, PK and Khan, J and Mallesh, R and Garg, S and Gupta, S and Jaisankar, P and Ghosh, S},
title = {Discovery of Carbazole and Theophylline-Based Amyloid Inhibitor for the Promotion of Neuroprotection.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00067},
pmid = {40445128},
issn = {1948-7193},
abstract = {The amyloid-beta 42 (Aβ42) peptide assembles into neurotoxic soluble oligomers and extracellular fibrillary aggregates during the progression of Alzheimer's disease (AD), which ultimately leads to amyloid plaque in the brain, causing major disruption of the neural circuit and leading to the severe loss of memory. Thus, perturbation or inhibition of this process through the development of advanced inhibitors is crucial for the treatment of AD. Here, we adopted an advanced strategy that showcases the design of a carbazole-based chemical inhibitor targeting the Aβ peptide. The new inhibitors are designed in such a way that they can bind selectively with the Aβ42 peptide and inhibit the assembly process and disease progression. Initial assessments using the thioflavin-T assay and molecular docking experiments help screen the carbazole and theophylline-based CT-01 as effective lead molecules, which bind at the N-terminal hydrophobic region of the Aβ42 peptide and inhibit the formation of soluble oligomers and extracellular fibrillary aggregates. Further, FT-IR spectroscopy, CD, TEM, dot blot, and ITC experiments suggest the inhibition potency of CT-01. Finally, the neuroprotection and apoptosis assay confirm that CT-01 reduces amyloid-mediated toxicity in neurons. The serum-stable CT-01 can also protect the NGF-deprived neurons and has the ability to cross the blood-brain barrier.},
}

@article {pmid40445088,
year = {2025},
author = {Miao, J and Huang, Y and Yi, Q and Wang, Y and Xiao, S and Liu, Y and Yang, C and Li, X and Tian, L and He, K and Li, J},
title = {Metabolomics and network pharmacology based study of the potential of Brassica rapa L. extract BREE-Ea for the treatment of Alzheimer's disease.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5fo01180a},
pmid = {40445088},
issn = {2042-650X},
abstract = {Background: Alzheimer's disease (AD) is a severe neurodegenerative disorder causing memory loss, cognitive decline, and behavioral changes. The disease mechanisms involve oxidative stress, inflammation, and abnormal protein aggregation. BREE-Ea, a bioactive compound derived from Brassica rapa L. (BR)-a traditional food crop indigenous to the Xinjiang Uygur Autonomous Region, where it has been cultivated as a vital local food source for centuries-has shown anti-inflammatory and antioxidant properties in in vivo experiments. Methods: An experimental study was conducted using an in vivo AD mouse model to evaluate the effects of BREE-Ea on memory loss and spatial discrimination deficits. Biochemical analyses were performed to assess antioxidant enzyme activities, oxidative stress markers, and inflammatory cytokines in the brains of AD mice. Metabolomics and network pharmacology approaches were used to identify blood- and brain-entry components and metabolic pathways involved. Molecular docking was also conducted to confirm the binding affinity of these components to their targets. Results: Treatment with BREE-Ea at a dose of 20 mg kg[-1] significantly improved memory loss and spatial discrimination deficits in AD mice. Biochemical analyses revealed that BREE-Ea enhanced antioxidant enzyme activities (SOD, GSH-Px, CAT) and reduced oxidative stress markers (MDA, AchE) and inflammatory cytokines (TNF-α, IL-6) in the brains of AD mice. Additionally, BREE-Ea decreased Aβ plaque deposition and Tau hyperphosphorylation, contributing to improved cognitive function. Metabolomics and network pharmacology approaches identified key therapeutic pathways such as serotonin synaptic transmission and neuroactive ligand-receptor interactions, targeting proteins like CASP3, APP, and PTGS2. Molecular docking confirmed the binding affinity of these components to their targets. Conclusion: BREE-Ea emerges as a highly promising therapeutic candidate for AD that effectively addresses the multifactorial nature of the disease and underscores its potential to alleviate the cognitive impairments associated with this debilitating condition.},
}

@article {pmid40444644,
year = {2025},
author = {Choi, M and Jin, BH and Keum, DH and Mo, KH and Park, MS and Lee, J and Park, S and Kim, CO},
title = {Bioequivalence of a Donepezil/Memantine 10/20 mg Fixed-Dose Combination Versus Single-Component Tablets in Healthy Korean Males.},
journal = {Clinical pharmacology in drug development},
volume = {},
number = {},
pages = {},
doi = {10.1002/cpdd.1556},
pmid = {40444644},
issn = {2160-7648},
abstract = {A fixed-dose combination (FDC) tablet formulation of donepezil/memantine (10/20 mg) was developed to improve medication compliance in patients with Alzheimer's disease (AD). This study compared the pharmacokinetic (PK) characteristics and safety profiles of an FDC formulation (donepezil/memantine [10/20 mg]) and single components (SCs) of donepezil (10 mg) and memantine (20 mg). In a randomized, open-label, single-dose, 2-way crossover study, 24 healthy Korean participants received a single oral dose of FDC in 1 period and an SC of donepezil and memantine in another period. For PK analysis, blood samples were collected up to 240 hours after administration. The geometric mean ratios and their 90% confidence intervals for the main PK parameters (Cmax and AUClast) indicated PK equivalence between the FDC and SC formulations. Regarding the safety profile, all adverse events were mild, with no serious adverse events. These findings support the use of an FDC formulation as a viable alternative to SCs of donepezil and memantine, potentially improving treatment adherence in patients with moderate-to-severe AD.},
}

@article {pmid40444618,
year = {2025},
author = {Singh, H and Pandey, VP},
title = {Phytoconstituents as Potential Therapeutics against Enzymatic Targets for Neurodegenerative Diseases.},
journal = {Current protein & peptide science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892037350938250514110643},
pmid = {40444618},
issn = {1875-5550},
abstract = {Neurodegenerative diseases are brought on by the loss of function of nerve cells in the brain or peripheral nervous system and afflict millions of people worldwide. Parkinson's disease and Alzheimer's disease are the two most common neurodegenerative diseases. These neurodegenerative diseases are multi-factorial, progressive, age-related, and influenced by two factors: genetic and environmental. Successful treatment of neurodegenerative diseases is yet a challenging task due to lack of selectivity, toxicity, and the growth of multi-drug-resistant cells to the currently available drugs. Plant-derived, natural secondary metabolites have a significant impact on the research and development of novel medications against neurodegenerative disease. Plant-derived natural products are frequently regarded as safe and relatively safer substitutes for synthetic drugs. The present review deals with the elucidation of plant-derived secondary metabolites, namely alkaloids, flavonoids, and terpenoids, as anti-neurological therapeutics with special reference to various enzymatic targets, such as β-secretase, γ-secretase, α-Secretase, acetylcholinesterase, monoamine oxidase, and phosphodiesterase-4.},
}

@article {pmid40444455,
year = {2025},
author = {Jo, Y and Kim, Y and Kang, R and Lee, S and Nguyen, DD and Park, S and Lee, D and Han, JW and Mook-Jung, I and Lee, LP and Park, JC and Kim, I},
title = {Monitoring the Dynamics of Alzheimer's Disease Biomarkers and the APOE-Tau Axis via Human Cerebral Organoids with Immuno-SERS.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e05660},
doi = {10.1002/advs.202505660},
pmid = {40444455},
issn = {2198-3844},
support = {RS-2023-00266110//National Research Foundation/ ; RS-2024-00462912//National Research Foundation/ ; RS-2021-NR061797//NRF Sejong Science Fellowship/ ; RS-2022-NR072469//NRF Sejong Science Fellowship/ ; //HK Lee Foundation/ ; RS-2024-00339665//Korea Dementia Research Center/ ; },
abstract = {Noninvasive monitoring of Alzheimer's disease (AD) biomarkers is essential for early diagnosis and treatment efficacy. However, noninvasive monitoring of tau protein secretion, a key biomarker of AD, across developmental stages, age-related variations, and the interaction between apolipoprotein E (APOE) and the tau protein axis is not yet accomplished. Here, the label-free and non-invasive detection of multiple tau variants dynamics across developmental stages, age-related variants, and various APOE isogenic genotyes is presented to investigate the APOE-tau axis using human cerebral organoids (hCOs) combined with surface-enhanced Raman spectroscopy (SERS). Principal component analysis (PCA) of SERS signals successfully identifies four developmental stages of hCOs: embryonic body, neuronal differentiation, maturation, and maintenance phases. Temporal dynamics of age-related tau protein secretion are observed, reflecting characteristics associated with AD, which are diminished by astrocyte expression. PCA-based dimensionality reduction of SERS signals further reveals distinct clustering for different APOE isogenic genotypes, with tau protein secretion increasing from APOE2/E2 to APOE4/E4, providing direct insight into the APOE-tau axis in AD. This study introduces a novel method for the non-invasive clinical assessments of disease conditions, dynamics, and the relationship between APOE and tau in AD.},
}

@article {pmid40444055,
year = {2025},
author = {Rastinpour, Z and Fakhri, S and Abbaszadeh, F and Ranjbari, M and Kiani, A and Namiq Amin, M and Echeverría, J},
title = {Neuroprotective effects of astaxanthin in a scopolamine-induced rat model of Alzheimer's disease through antioxidant/anti-inflammatory pathways and opioid/benzodiazepine receptors: attenuation of Nrf2, NF-κB, and interconnected pathways.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1589751},
pmid = {40444055},
issn = {1663-9812},
abstract = {BACKGROUND: Given the complexity of pathological mechanisms behind Alzheimer's disease (AD), there is a pressing need for novel multi-targeting therapeutic agents. Astaxanthin, a natural compound with diverse biological effects, has emerged as a potential candidate in neuronal diseases.

PURPOSE: This study aimed to evaluate the neuroprotective effects of astaxanthin in a scopolamine-induced rat model of AD.

MATERIALS AND METHODS: In total, 36 male Wistar rats were divided into six groups, including a control group receiving normal saline, a negative control group treated with scopolamine (1 mg/kg), and two groups receiving astaxanthin at doses of 5 and 10 mg/kg. Additionally, two groups were pre-treated with naloxone (0.1 mg/kg) or flumazenil (0.5 mg/kg) to block opioid and benzodiazepine receptors, respectively, followed by receiving the most effective dose of astaxanthin (i.e., 10 mg/kg). Treatments were administered via intraperitoneal injection for 14 consecutive days and behavioral tests were done. Biochemical analyses, zymography, Western blotting, and histopathological examinations were also performed.

RESULTS AND DISCUSSION: Astaxanthin treatment significantly improved cognitive function, enhanced plasma antioxidant capacity by increasing catalase and glutathione levels, and reduced nitrite levels. It also increased serum activity of matrix metalloproteinase 2 (MMP-2), while decreasing MMP-9, increasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2) and decreasing nuclear factor kappa B (NF-κB) in hippocampal tissue. Histopathological findings indicated reduced hippocampal damage after astaxanthin administration. The aforementioned protective effects of astaxanthin were reversed by naloxone and flumazenil.

CONCLUSION: Astaxanthin demonstrates protective effects against scopolamine-induced AD through its neuroprotective, antioxidant, and anti-inflammatory properties, potentially involving interactions with opioid and benzodiazepine receptors.},
}

@article {pmid40444050,
year = {2025},
author = {Sarti, G and Traini, C and Magni, G and Attorre, S and Tognozzi, G and Calussi, E and Giovannini, MG and Vannucchi, MG and Lana, D},
title = {Chronic administration of prebiotics and probiotics prevent pathophysiological hallmarks of Alzheimer's disease in the cortex of APP/PS1 mice.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1596469},
pmid = {40444050},
issn = {1663-9812},
abstract = {INTRODUCTION: Dysbiosis is a characteristic of patients with Alzheimer's disease (AD). The disbalance between Gram-negative and Gram-positive bacteria causes increased production of beta-amyloid (Aβ) in the gut, which can contribute to brain accumulation of Aβ. Recovering microbiota composition with symbiotic administration of prebiotics and probiotics may be a strategy to prevent or reduce AD symptomathology. The aim of this research was to study whether chronic administration of pre- and probiotics modifies the histopathological signs of neurodegeneration in the cortex of APP/PS1 mice, a transgenic mouse model of AD. We focused on neuritic plaques deposition, neuronal degeneration and glia activation.

METHODS: Transgenic (TG) mice and Wild type (WT) littermates were fed daily with a diet supplemented with prebiotics (a multi-extract of fibers and plant complexes, containing inulin/fruit-oligosaccharides) and probiotics (a 50%-50% mixture of Lactobacillus rhamnosus and Lactobacillus paracasei). The treatment started at 2 months of age and lasted for 6 months. Controls were WT and TG mice fed with a standard diet. All groups were evaluated qualitatively and quantitatively by immunofluorescence, confocal microscopy and digital imaging. Cortical sections were immunostained for neuritic plaques, neurons, astrocytes, microglia, and inflammatory proteins. Qualitative and quantitative analyses were carried out by immunofluorescence, confocal microscopy and digital imaging with ImageJ software.

RESULTS: Quantitative analyses in TG mice demonstrated intense Aβ load and accumulation of neurofilament heavy polypeptide (NHP) in neuritic plaques, neuronal degeneration, shrinkage of the cortex, increase of GFAP expression, and microglia and astrocytes activation. All these effects were mainly evident in cortical Layer 5. The symbiotic treatment with pre- and probiotics decreased Aβ deposition and neuritic plaques in the frontoparietal cortex. In addition, the treatment decreased the degeneration of neurons, the cortical shrinkage, increased GFAP expression, and modified microglia phenomic, decreasing significantly microglia activation. The abovementioned effects of the treatment were mostly evident in cortical Layer 5.

DISCUSSION: These data confirm that prolonged dietary regimen enriched with pre- and probiotics counteracts many of the histopathological hallmarks of AD, and poses the bases for a simple, affordable treatment that may help prevent AD.},
}

@article {pmid40443793,
year = {2025},
author = {Park, Y and Moon, S and Jung, H and Park, S and Kim, JW and Song, DG and In, YH and Han, SW and Sohn, JH and Lee, CH},
title = {Mirodenafil improves cognitive function by reducing microglial activation and blood-brain barrier permeability in ApoE4 KI mice.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1579411},
pmid = {40443793},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) has significant public health concerns in the aging society. AD can compromise brain function and lead to severe neurological abnormalities associated with dementia. The human Apolipoprotein E (ApoE4) gene is a strong risk factor for AD. However, comprehensive analyses and improvements of mouse models expressing ApoE4 remain largely unexplored.

METHODS: ApoE4 knock-in (KI) mice were used to investigate the role of humanized ApoE4 in hippocampal histological changes and cognitive impairment. Cerebrovascular perfusion, blood-brain barrier (BBB) integrity, microgliosis, and amyloid-beta 42 (Aβ42) accumulation were examined. Cognitive functions were assessed using the Morris water maze, Y-maze, and novel object recognition tests. Mirodenafil, a potent and selective phosphodiesterase 5 inhibitor (PDE5i), was orally administered to ApoE4 KI mice for 4 weeks. An in vitro BBB model and BV2 microglial cells were used to investigate endothelial permeability and inflammation.

RESULTS: ApoE4 KI mice exhibited not only reduced cerebrovascular perfusion and CLN-5 expression but also increased microgliosis and Aβ42 accumulation in the hippocampus. These phenomena were accompanied by impaired cognitive functions. Mirodenafil administration reversed the histological and behavioral alterations induced by ApoE4 KI. In vitro, mirodenafil treatment mitigated Aβ42-induced endothelial permeability and lipopolysaccharide-induced microglial inflammation.

DISCUSSION: These findings suggest that mirodenafil enhances cerebrovascular function, preserves BBB integrity, and mitigates neuroinflammation in ApoE4 KI mice, leading to cognitive improvement. PDE5 inhibition may serve as a promising therapeutic approach for addressing ApoE4-associated cerebrovascular and cognitive dysfunction.},
}

@article {pmid40443709,
year = {2025},
author = {Dolciotti, C and Righi, M and Grecu, E and Trucas, M and Maxia, C and Murtas, D and Diana, A},
title = {The translational power of Alzheimer's-based organoid models in personalized medicine: an integrated biological and digital approach embodying patient clinical history.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1553642},
pmid = {40443709},
issn = {1662-5102},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition characterized by a multifaceted interplay of genetic, environmental, and pathological factors. Traditional diagnostic and research methods, including neuropsychological assessments, imaging, and cerebrospinal fluid (CSF) biomarkers, have advanced our understanding but remain limited by late-stage detection and challenges in modeling disease progression. The emergence of three-dimensional (3D) brain organoids (BOs) offers a transformative platform for bridging these gaps. BOs derived from patient-specific induced pluripotent stem cells (iPSCs) mimic the structural and functional complexities of the human brain. This advancement offers an alternative or complementary approach for studying AD pathology, including β-amyloid and tau protein aggregation, neuroinflammation, and aging processes. By integrating biological complexity with cutting-edge technological tools such as organ-on-a-chip systems, microelectrode arrays, and artificial intelligence-driven digital twins (DTs), it is hoped that BOs will facilitate real-time modeling of AD progression and response to interventions. These models capture central nervous system biomarkers and establish correlations with peripheral markers, fostering a holistic understanding of disease mechanisms. Furthermore, BOs provide a scalable and ethically sound alternative to animal models, advancing drug discovery and personalized therapeutic strategies. The convergence of BOs and DTs potentially represents a significant shift in AD research, enhancing predictive and preventive capacities through precise in vitro simulations of individual disease trajectories. This approach underscores the potential for personalized medicine, reducing the reliance on invasive diagnostics while promoting early intervention. As research progresses, integrating sporadic and familial AD models within this framework promises to refine our understanding of disease heterogeneity and drive innovations in treatment and care.},
}

@article {pmid40443428,
year = {2024},
author = {Shri, SR and Nayak, Y and Ranganath Pai, S},
title = {Molecular docking studies and molecular dynamic simulation analysis: To identify novel ATP-competitive inhibition of Glycogen synthase kinase-3β for Alzheimer's disease.},
journal = {F1000Research},
volume = {13},
number = {},
pages = {773},
pmid = {40443428},
issn = {2046-1402},
mesh = {*Alzheimer Disease/drug therapy/enzymology ; *Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/chemistry/metabolism ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; Humans ; *Adenosine Triphosphate/metabolism ; *Protein Kinase Inhibitors/pharmacology/chemistry ; Ligands ; },
abstract = {BACKGROUND: The discovery of an ideal and effective therapy is urgently required for the treatment of Alzheimer's disease. The main pathological hallmarks of Alzheimer's disease that appear before the clinical symptoms are neurofibrillary tangles, amyloid plaques, brain inflammation, and neuronal atrophy throughout the cerebral cortex and hippocampus. GSK-3β (Glycogen Synthase Kinase-3β) is regarded as the most important and promising target for therapeutic use because GSK-3β expression levels increase with age and are the most abundant and hyperactive in the brains of patients with Alzheimer's disease.

METHODS: We used Maestro, which is Schrodinger, for our computational simulation studies. In the present work, we have used different modules that were used in previous studies with a little modification, the modules such as Protein Preparation with the help of Protein Preparation Wizard, Ligand Preparation with the help of LigPrep, for ADME (Absorption, Distribution, Metabolism and Excretion) prediction we used Qikprop, Docking studies we used Glide module, Binding energy prediction we used Prime and Molecular dynamic simulation studies by Desmond.

RESULTS: Our focus is mainly on an in-silico approach, focusing on library generation; we first drew an imidazo [1,5-a]pyridine-3-carboxamide (IMID 2) scaffold structure at Enamine and subjected it to a substructure search to target the receptor grid region (ATP-competitive site) of 6Y9R. They were then subjected to various screening processes. Finally, we selected nine compounds and subjected them to molecular dynamic simulation studies.

CONCLUSIONS: Nine compounds showed good results with the most stable interactions. Further experiments and studies are required to confirm these results.},
}

*Alzheimer Disease/drug therapy/enzymology
*Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/chemistry/metabolism
*Molecular Dynamics Simulation
*Molecular Docking Simulation
Humans
*Adenosine Triphosphate/metabolism
*Protein Kinase Inhibitors/pharmacology/chemistry
Ligands

@article {pmid40442885,
year = {2025},
author = {Wu, CK and Fuh, JL},
title = {A 2025 update on treatment strategies for the Alzheimer's disease spectrum.},
journal = {Journal of the Chinese Medical Association : JCMA},
volume = {},
number = {},
pages = {},
doi = {10.1097/JCMA.0000000000001252},
pmid = {40442885},
issn = {1728-7731},
abstract = {Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder with a continuum of stages ranging from preclinical/asymptomatic phase to severe dementia. Over the past decades, significant advances in diagnostic biomarkers and disease-modifying therapies have reshaped the treatment landscape. This review provides a comprehensive overview of the current treatment paradigm for AD in 2025, incorporating the latest developments in pharmacological and non-pharmacological interventions. The advent of anti-amyloid immunotherapy, including FDA-approved monoclonal antibodies such as lecanemab and donanemab, has proven efficacy in slowing cognitive decline in early-stage AD. These therapies mark a change in thinking in AD management, emphasizing the importance of early diagnosis and intervention. Cholinesterase inhibitors and memantine remain the standard treatments for mild, moderate to severe dementia, providing symptomatic relief and functional stabilization. Additionally, emerging strategies targeting tau pathology and neuroinflammation are under investigation, offering hope for future breakthroughs. Beyond pharmacotherapy, this review highlights the importance of personalized, multimodal treatment approaches that integrate lifestyle modifications, cognitive training, and caregiver support. The updated diagnostic framework, incorporating fluid and imaging biomarkers, enables more precise staging and individualized treatment plans. Despite these advances, challenges still lie in refining patient selection, addressing treatment-related side effects, and ensuring accessibility to appropriate therapies. As the field moves forward, ongoing clinical trials and real-world evidence will further refine treatment strategies. A proactive approach, combining early detection with disease-modifying and symptomatic therapies, is essential for improving patient outcomes and quality of life. This article synthesizes current knowledge and provides a roadmap for clinicians and researchers navigating the evolving landscape of AD treatment.},
}

@article {pmid40442871,
year = {2025},
author = {Kirsebom, BE and Gonzalez-Ortiz, F and Vigneswaran, S and Bråthen, G and Skogseth, RE and Gísladóttir, B and Harrison, P and Jarholm, JA and Pålhaugen, L and Rongve, A and Selnes, P and Tjims, B and Turton, M and Van Harten, AC and Waterloo, K and Zetterberg, H and Fladby, T and Blennow, K},
title = {Repeated plasma p-tau217 measurements to monitor clinical progression heterogeneity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {5},
pages = {e70319},
doi = {10.1002/alz.70319},
pmid = {40442871},
issn = {1552-5279},
support = {NRC 311993//Norwegian Research Council/ ; #2023-00356//Swedish Research Council/ ; #2022-01018//Swedish Research Council/ ; #2019-02397//Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #201809-2016862//Alzheimer Drug Discovery Foundation/ ; //AD Strategic Fund/ ; #ADSF-21-831376-C//the Alzheimer's Association/ ; #ADSF-21-831381-C//the Alzheimer's Association/ ; #ADSF-21-831377-C//the Alzheimer's Association/ ; #ADSF-24-1284328-C//the Alzheimer's Association/ ; //European Partnership on Metrology/ ; #22HLT07//Participating States/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; //Stiftelsen för Gamla Tjänarinnor/ ; #FO2022-0270//Hjärnfonden/ ; 860197//Marie Skłodowska-Curie/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; //National Institute for Health/ ; //Care Research University College London Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute/ ; #2017-00915//UK Dementia Research Institute/ ; #2022-00732//UK Dementia Research Institute/ ; #AF-930351//Swedish Alzheimer Foundation/ ; #AF-939721//Swedish Alzheimer Foundation/ ; #AF-968270//Swedish Alzheimer Foundation/ ; #AF-994551//Swedish Alzheimer Foundation/ ; #ALZ2022-0006//Swedish Alzheimer Foundation/ ; #FO2024-0048-TK-130//Swedish Alzheimer Foundation/ ; #ALFGBG-965240//Swedish Alzheimer Foundation/ ; #ALFGBG-1006418//Swedish Alzheimer Foundation/ ; JPND2019-466-236//European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//European Union Joint Program for Neurodegenerative Disorders/ ; SG-23-1038904 QC//European Union Joint Program for Neurodegenerative Disorders/ ; //La Fondation Recherche Alzheimer (FRA)/ ; //Kirsten and Freddy Johansen Foundation/ ; //Copenhagen/ ; //Familjen Rönströms Stiftelse/ ; },
mesh = {Humans ; *tau Proteins/blood ; *Disease Progression ; Male ; Female ; *Cognitive Dysfunction/blood ; *Alzheimer Disease/blood ; Aged ; Amyloid beta-Peptides ; Phosphorylation ; Biomarkers/blood ; Cohort Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Heterogeneity of clinical progression in Alzheimer's disease (AD) complicates the assessment of disease progression and treatment effects in trials. This study evaluates the potential of plasma phosphorylated tau-217 (p-tau217) to capture this heterogeneity.

METHODS: We used k-means clustering to analyze cognitive trajectories in amyloid beta -positive (Aβ+) cognitively normal (CN) and mild cognitive impairment (MCI) participants from two independent cohorts. Cohort 1 included 186 participants (71 CN, 115 MCI; 507 observations) and Cohort 2 included 207 participants (64 CN, 144 MCI; 781 observations), both with up to 10 years of follow-up.

RESULTS: Three progression clusters emerged in both cohorts: stable cognition, slow decline, and rapid decline-each including cases initially classified as CN or MCI. Baseline plasma p-tau217 was linked to progression risk in both cohorts, whereas longitudinal increases in Cohort 1 were steepest in rapid decliners.

DISCUSSION: Plasma p-tau217 may aid in capturing clinical heterogeneity and support stratification and monitoring of disease progression in clinical trials.

HIGHLIGHTS: k-Means found stable, slow, and rapid cognitive decline clusters in amyloid beta-positive (Aβ+) cases. Higher baseline plasma phosphorylated tau-217 (p-tau217) levels predicted faster cognitive decline. Longitudinal increases in plasma p-tau217 were steepest in rapid decliners. Plasma p-tau217 tracks clinical progression heterogeneity in Aβ+ cases. Cognitive stage and amyloid alone may miss severity and risk in early-stage Alzheimer's disease.},
}

Humans
*tau Proteins/blood
*Disease Progression
Male
Female
*Cognitive Dysfunction/blood
*Alzheimer Disease/blood
Aged
Amyloid beta-Peptides
Phosphorylation
Biomarkers/blood
Cohort Studies
Aged, 80 and over

@article {pmid40442822,
year = {2025},
author = {Latina, V and De Introna, M and Malerba, F and Florio, R and Balzamino, BO and Di Natale, G and Sciacca, MFM and Pappalardo, G and Micera, A and Pignataro, A and Calissano, P and Amadoro, G},
title = {Acute targeting of N-terminal tau protein has long-lasting beneficial effects in Tg2576 APP/Aβ mouse model by reducing cognitive impairment, cerebral Aβ-amyloidosis, synaptic remodeling and microgliosis later in life.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {121},
pmid = {40442822},
issn = {2051-5960},
support = {RC278859//Italian Ministry of Health/ ; RF-2021-12374301//Italian Ministry of Health/ ; FOE D.M865/2019//Fondo Ordinario Enti funds in the framework of a collaboration agreement between the Italian National Research Council and EBRI/ ; FOE D.M865/2019//Fondo Ordinario Enti funds in the framework of a collaboration agreement between the Italian National Research Council and EBRI/ ; Proposal ID: 971925//Alzheimer's Association Research Grant/ ; },
mesh = {Animals ; *tau Proteins/metabolism/immunology ; Mice, Transgenic ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics/metabolism ; Amyloid beta-Peptides/metabolism ; Mice ; *Alzheimer Disease/pathology/drug therapy/metabolism ; *Cognitive Dysfunction/pathology/drug therapy/metabolism ; *Gliosis/pathology/drug therapy ; *Antibodies, Monoclonal/pharmacology/therapeutic use ; Humans ; *Amyloidosis/pathology ; *Synapses/pathology/drug effects ; Male ; Microglia/pathology/drug effects ; Brain/pathology/metabolism ; Female ; },
abstract = {Even though the number of patients suffering from Alzheimer's Disease (AD) is rapidly growing worldwide, only a few symptomatic treatments have been approved for clinical use, pointing out the urgent need for more effective disease-modifying therapies that actually alter the progression of this neurodegenerative disorder which is characterized by co-occurence of both Amyloid beta (Aβ) and tau neuropathologies. Preclinical and clinical evidence suggests that a link between Aβ and tau drives the entire continuum of AD pathobiology. 12A12 is a monoclonal antibody (mAb) which offers neuroprotection into two transgenic lines of AD, including Tg2576 that overexpresses Swedish mutation (KM670/671NL) of Amyloid Precursor Protein (APP, isoform 695) and 3xTg (APP Swedish, MAPT P301L, and PSEN1 M146V), by targeting the 20-22kDa N-terminal tau fragments (NH2htau). In particular, acute (over 14 days with 4 doses), intravenous injection of 12A12mAb leads to significant improvement of cognitive, biochemical and histopathological AD signs in symptomatic 6-month-old Tg2576, a well-established transgenic mouse model that mimics the human amyloidosis with an age-dependent Aβ accumulation/aggregation and plaque deposition. Here, we report that Tg2576 mice, immunized with 12A12mAb at 6 months of age and returned to their home cage for additional 3 months, exhibit preserved spatial memory despite the anticipated interruption of antibody administration (discontinuous treatment). This enduring beneficial effect on memory deficit (up to 90 days after the last injection) is accompanied by normalization in the synaptic imbalance and microgliosis along with decrease of the most toxic A11-positive prefibrillar oligomers and inverse increase in 4kDa monomeric form(s) of Aβ 1-42. These findings reveal that: (i) soluble, pathogenetic tau specie(s) located at the N-terminal domain of protein early synergizes with Aβ in driving the progression of AD neuropathology; (ii) transient immunoneutralization of the NH2htau following short-term treatment with 12A12mAb exerts preventive, long-lasting neuroprotective effects, at least in part by interfering at "pre-plaque" stage with the progressive deposition of insoluble, fibrillar Aβ via a shift of its aggregation pathway into its less harmful, unaggregated monomeric forms. Taken together, these findings represent a strong rationale for the advancement of 12A12mAb to clinical stage aiming at preventing the Aβ-dependent neurodegeneration by lowering the cerebral levels of NH2htau in humans suffering from chronic, slow-progressing AD.},
}

Animals
*tau Proteins/metabolism/immunology
Mice, Transgenic
Disease Models, Animal
Amyloid beta-Protein Precursor/genetics/metabolism
Amyloid beta-Peptides/metabolism
Mice
*Alzheimer Disease/pathology/drug therapy/metabolism
*Cognitive Dysfunction/pathology/drug therapy/metabolism
*Gliosis/pathology/drug therapy
*Antibodies, Monoclonal/pharmacology/therapeutic use
Humans
*Amyloidosis/pathology
*Synapses/pathology/drug effects
Male
Microglia/pathology/drug effects
Brain/pathology/metabolism
Female

@article {pmid40442550,
year = {2025},
author = {Wongjaikam, S and Siengdee, P and Somnus, A and Govitrapong, P},
title = {Melatonin Alleviates Erastin-Induced Cell Death by Inhibiting Ferroptosis and Amyloid Precursor Protein Processing in Neuronal Cell Lines.},
journal = {Neurotoxicity research},
volume = {43},
number = {3},
pages = {25},
pmid = {40442550},
issn = {1476-3524},
mesh = {*Ferroptosis/drug effects/physiology ; Humans ; *Amyloid beta-Protein Precursor/metabolism ; *Melatonin/pharmacology ; Cell Line, Tumor ; *Neurons/drug effects/metabolism ; *Piperazines/toxicity ; Cell Death/drug effects/physiology ; Reactive Oxygen Species/metabolism ; Lipid Peroxidation/drug effects ; Aldehydes/metabolism ; Iron/metabolism ; *Antioxidants/pharmacology ; Cell Survival/drug effects/physiology ; Phenylenediamines/pharmacology ; Amyloid Precursor Protein Secretases/metabolism ; Cyclohexylamines ; },
abstract = {Ferroptosis is an iron-dependent and membrane lipid peroxidation-mediated form of programmed or regulated cell death. A number of recent studies have demonstrated that ferroptosis contributes to Alzheimer's disease (AD)-mediated nerve cell death. Melatonin demonstrates strong antioxidant properties and offers protective benefits for the brain in the context of AD. However, it is not fully known whether melatonin protects against ferroptosis and whether ferroptosis affects amyloid precursor protein (APP) processing. In this study, we studied the effects of melatonin on SH-SY5Y cells-induced ferroptosis using erastin, and ferrostatin-1 was used as a ferroptosis inhibitor. To confirm the occurrence of ferroptosis, we conducted measurements of cell cytotoxicity, intracellular iron, reactive oxygen species (ROS), and 4-hydroxynonenal (4-HNE). The protein expressions that were regulated by either ferroptosis or APP processing were measured. Our results revealed that erastin increased intracellular iron levels, ROS, and 4-HNE lipid peroxidation in SH-SY5Y cells, resulting in an increased percentage of cell death. Erastin disrupted the regulation of proteins involved in ferroptosis and increased the production of amyloid beta (Aβ) through APP proteolysis. Following melatonin treatment, intracellular iron, ROS, and 4-HNE levels were significantly reduced. Additionally, the cystine/glutamate antiporter (system xc[-]) and glutathione peroxidase 4 (GPX4) were increased, and acyl-CoA synthetase long chain family member 4 (ACSL4) was diminished. APP, β-site-APP cleaving enzyme 1 (BACE1), presenilin 1 (PS1) and Aβ production were alleviated in erastin-treated SH-SY5Y cells. In conclusion, melatonin effectively inhibits ferroptosis-related cell death and AD-like conditions induced by erastin in SH-SY5Y human neuroblastoma cell lines.},
}

*Ferroptosis/drug effects/physiology
Humans
*Amyloid beta-Protein Precursor/metabolism
*Melatonin/pharmacology
Cell Line, Tumor
*Neurons/drug effects/metabolism
*Piperazines/toxicity
Cell Death/drug effects/physiology
Reactive Oxygen Species/metabolism
Lipid Peroxidation/drug effects
Aldehydes/metabolism
Iron/metabolism
*Antioxidants/pharmacology
Cell Survival/drug effects/physiology
Phenylenediamines/pharmacology
Amyloid Precursor Protein Secretases/metabolism
Cyclohexylamines

@article {pmid40442293,
year = {2025},
author = {Nakata, K and Sakamoto, J and Otomo, K and Sato, M and Ishii, H and Tsutsumi, M and Enoki, R and Nemoto, T},
title = {Amyloid-β-induced alteration of fast and localized calcium elevations in cultured astrocytes.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {18944},
pmid = {40442293},
issn = {2045-2322},
mesh = {*Astrocytes/metabolism/drug effects ; *Amyloid beta-Peptides/metabolism/pharmacology ; *Calcium/metabolism ; Animals ; Cells, Cultured ; Calcium Signaling ; Alzheimer Disease/metabolism/pathology ; Glutamic Acid/metabolism ; Rats ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes cognitive decline. Uncovering the mechanisms of neurodegeneration in the early stages is essential to establish a treatment for AD. Recent research has proposed the hypothesis that amyloid-β (Aβ) oligomers elicit an excessive glutamate release from astrocytes toward synapses through intracellular free Ca[2+] ([Ca[2+]]i) elevations in astrocytes, finally resulting in neuronal dendritic spine loss. Under physiological conditions, astrocytic [Ca[2+]]i elevations range spatially from microdomains to network-wide propagation and temporally from milliseconds to tens of seconds. Astrocytic localized and fast [Ca[2+]]i elevations might correlate with glutamate release; however, the Aβ-induced alteration of localized, fast astrocytic [Ca[2+]]i elevations remains unexplored. In this study, we quantitatively investigated the Aβ dimers-induced changes in the spatial and temporal patterns of [Ca[2+]]i in a primary culture of astrocytes by two-photon excitation spinning-disk confocal microscopy. The frequency of fast [Ca[2+]]i elevations occurring locally in astrocytes (≤ 0.5 s, ≤ 35 µm[2]) and [Ca[2+]]i event occupancy relative to cell area significantly increased after exposure to Aβ dimers. The effect of Aβ dimers appeared above 500 nM, and these Aβ dimers-induced [Ca[2+]]i elevations were primarily mediated by a metabotropic purinergic receptor (P2Y1 receptor) and Ca[2+] release from the endoplasmic reticulum. Our findings suggest that the Aβ dimers-induced alterations and hyperactivation of astrocytic [Ca[2+]]i is a candidate cellular mechanism in the early stages of AD.},
}

*Astrocytes/metabolism/drug effects
*Amyloid beta-Peptides/metabolism/pharmacology
*Calcium/metabolism
Animals
Cells, Cultured
Calcium Signaling
Alzheimer Disease/metabolism/pathology
Glutamic Acid/metabolism
Rats

@article {pmid40441521,
year = {2025},
author = {Vijayan, V and Siddique, IA and Gupta, S and Chopra, EM and Raj, N and Surolia, A and Gupta, S},
title = {Osteocalcin modulates Abeta42 aggregation to aid in amyloid reduction in mouse models of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115322},
doi = {10.1016/j.expneurol.2025.115322},
pmid = {40441521},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by overexpression of amyloid-beta in the brain, particularly the toxic Abeta-42 form. Recent studies have identified osteocalcin, a peptide traditionally associated with bone, to modulate cognitive function in the AD brain. Osteocalcin exists in two forms: the undercarboxylated (uOC) and carboxylated (cOC) forms. This study investigates the role of uOC in modulating Abeta42 aggregation and its potential therapeutic implications for AD. Administration of uOC, but not cOC, improved both spatial learning and exploratory behavior of 5xFAD transgenic Alzheimer mice. Further investigation showed that uOC reduced the level of insoluble Abeta42 in the brain and increased the level of soluble Abeta42. There was increase in mRNA levels of CD36 in uOC treated 5xFAD transgenic brain alongside upregulation of neuroprotectants like Adipoq and Ahsg (fetuin). We explored the mechanisms underlying the influence of uOC on Aβ42 dynamics and understood that uOC interacts with Glu residues to form non-toxic early tube-like intermediates (A-O) before advancing to late mature Abeta42 fibrils. These intermediates enable Abeta42 uptake by glial cells by upregulating the cell surface expression of CD36 and reducing TNF-alpha production. Collectively, the study sheds light on the fact that uOC modulates Abeta42 dynamics and this interaction is warranted for Abeta42 uptake and clearance. The study provides a novel dimension for the treatment of amyloid disorders like AD.},
}

@article {pmid40441463,
year = {2025},
author = {Li, B and Wang, J and Wang, B and Wang, X and Zhu, G and Yang, S},
title = {Therapeutic Potential of Genus Polygonatum in Common Neuropsychiatric Disorders: The Revival of an Ancient Remedy in Modern Medicine.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120052},
doi = {10.1016/j.jep.2025.120052},
pmid = {40441463},
issn = {1872-7573},
abstract = {Polygonatum is a genus within the family Asparagaceae, widely utilized in traditional medicine. Modern studies have substantiated its pharmacological properties, including anti-aging, neuroprotective, immunomodulatory, anti-diabetic, memory-enhancing, anti-inflammatory, and antioxidant effects. Recently, research on Polygonatum in the neuropsychiatric disorders has increased.

AIM OF STUDY: This review aims to provide a comprehensive summary of the medicinal plants and prescriptions from Polygonatum in the neuropsychiatric disorders, chemical components, and pharmacological and toxicological research evidence. It provides an extensive reference for the development of Polygonatum medicinal resources and the advancement of research in neuropsychiatric therapeutics.

METHODS: A comprehensive literature review was conducted using databases such as PubMed, Science Direct, Web of Science, and CNKI, along with sources like the "Chinese Pharmacopoeia" and other herbal medicine books. Keywords such as "Polygonatum", "neurological disorders", "Alzheimer's disease", and "toxicity" were employed to collate evidence of the traditional therapeutic effects, phytochemistry, pharmacology, and toxicology of Polygonatum species.

RESULTS: The genus Polygonatum comprises 86 species, of which 36 are medicinally utilized. There are 47 prescriptions containing Polygonatum species relevant to the prevention and treatment of neuropsychiatric disorders. A total of 427 compounds have been isolated from this genus, including 83 polysaccharides, 176 saponins, 83 flavonoids, 47 alkaloids, and 38 other components. The pharmacological actions of Polygonatum herbs include anti-aging, neuroprotection, sleep promotion, immune modulation, anti-fatigue, anti-diabetic, memory enhancement, anti-inflammatory, and antioxidant effects, showing improvement in conditions such as Alzheimer's disease, Parkinson's disease, vascular dementia, depression, sleep disorders, and post-traumatic stress disorder, with no apparent toxicity.

CONCLUSION: Polygonatum herbs hold potential as therapeutic agents for neuropsychiatric disorders, presenting significant implications for the development of neurological drugs and the utilization of medicinal plant resources.},
}

@article {pmid40439856,
year = {2025},
author = {Ebrahimi, R and Faramarzi, A and Salarvandian, S and Zarei, R and Heidari, M and Salehian, F and Esmaeilpour, K},
title = {Melatonin Supplementation in Alzheimer's disease: The Potential Role in Neurogenesis.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40439856},
issn = {1559-1182},
abstract = {Melatonin supplementation shows potential therapeutic effects in Alzheimer's disease (AD) by targeting impaired neurogenesis. Neurogenesis, the formation of new neurons after development, involves proliferation, migration, differentiation, and survival of neurons. Impaired neurogenesis is associated with AD, specifically in the subventricular zone (SVZ) and subgranular zone (SGZ), leading to hippocampal degeneration and memory impairment. Melatonin positively effects AD by regulating amyloid beta (Aβ)-induced neuroinflammation, reducing tau hyperphosphorylation, and enhancing adult neurogenesis through various signaling pathways. In addition, it has anti-apoptotic, antioxidative, and anti-inflammatory properties, suggesting its potential as a treatment option for AD progression. Furthermore, melatonin and sleep are closely linked, and an increase in sleep duration positively affects Aβ deposition. This review aims to examine the impact of AD pathologies on neurogenesis and explore the mechanisms by which melatonin may alleviate these pathologies, potentially promoting neurogenesis.},
}

@article {pmid40438877,
year = {2025},
author = {Alam, F and Banerjee, A and Jayawarna, C},
title = {Cerebral Amyloid Angiopathy: A Case Report.},
journal = {Cureus},
volume = {17},
number = {5},
pages = {e84989},
pmid = {40438877},
issn = {2168-8184},
abstract = {Cerebral amyloid angiopathy (CAA) is a cerebrovascular condition characterized by the buildup of beta-amyloid protein within the walls of small and medium-sized blood vessels in the brain's cortex and leptomeninges. Clinically, it can present with a range of neurological symptoms, including recurrent headaches, cognitive disturbances, seizures, and focal deficits. A key feature of CAA is the tendency for lobar brain hemorrhages, though its clinical and radiological profile can overlap with other neurological disorders such as Alzheimer's disease, demyelinating conditions, vascular syndromes, and neoplasms. CAA pathology is frequently observed in individuals with Alzheimer's disease, with a subset showing significant vascular involvement. Although histopathological confirmation remains definitive, advanced imaging, particularly MRI, has become central to diagnosis, often identifying features such as cortical microbleeds, superficial siderosis, and non-deep (lobar) hemorrhages. In some presentations, especially inflammatory variants, patients may benefit from immunosuppressive treatment such as corticosteroids, making early diagnosis critical. Recognizing the distinction between CAA-related hemorrhages and other causes of cerebral bleeding is vital for timely and appropriate management. We present a case of an elderly male who had multiple hospital presentations with unexplained self-resolving expressive dysphasia, seizure, and gradually increasing confusion with the possibility of underlying dementia that responded well to high-dose steroids. This case underscores the need to consider inflammatory cerebral amyloid angiopathy (iCAA) as a differential in patients with recurrent, unexplained neurological symptoms with CT evidence of micro- and macro-hemorrhages and a dramatic response to steroids for symptomatic improvement. Improved awareness of atypical presentations and the utility of MRI can support earlier intervention. Further investigation is needed to refine diagnostic tools, identify reliable biomarkers, and explore therapeutic strategies targeting the underlying vascular and inflammatory mechanisms of the disease.},
}

@article {pmid40438598,
year = {2025},
author = {Wang, K and Yang, R and Li, J and Wang, H and Wan, L and He, J},
title = {Nanocarrier-based targeted drug delivery for Alzheimer's disease: addressing neuroinflammation and enhancing clinical translation.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1591438},
pmid = {40438598},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-beta (Aβ) aggregation, tau pathology, and chronic neuroinflammation. Among these, neuroinflammation plays a crucial role in exacerbating disease progression, making it an attractive therapeutic target. However, the presence of the blood-brain barrier (BBB) significantly limits the effective delivery of therapeutic agents to the brain, necessitating novel drug delivery strategies. Nanocarrier-based delivery systems have emerged as a promising solution to these challenges, offering targeted drug transport, enhanced BBB penetration, and improved bioavailability while minimizing systemic toxicity. This review explores the current advancements in nanocarrier-mediated drug delivery for AD, focusing on the mechanisms of neuroinflammation, the role of nanocarriers in overcoming the BBB, and their ability to modulate inflammatory pathways. Furthermore, the review discusses preclinical validation strategies and key challenges, including safety concerns, large-scale production limitations, and regulatory hurdles that must be addressed to enable clinical translation. Future perspectives emphasize the integration of nanotechnology with precision medicine, gene therapy, and artificial intelligence to optimize nanocarrier design for individualized AD treatment. By overcoming these obstacles, nanocarriers hold the potential to revolutionize therapeutic approaches for AD and other neurodegenerative diseases.},
}

@article {pmid40438538,
year = {2025},
author = {Carrasco-Gómez, M and García-Colomo, A and Cabrera-Álvarez, J and Del Cerro-León, A and Gómez-Ariza, CJ and Santos, A and Maestú, F},
title = {Individual alpha frequency tACS reduces static functional connectivity across the default mode network.},
journal = {Frontiers in human neuroscience},
volume = {19},
number = {},
pages = {1534321},
pmid = {40438538},
issn = {1662-5161},
abstract = {INTRODUCTION: Research on the influence of transcranial alternating current stimulation over alpha functional connectivity (FC) is scarce, even when it poses as a potential treatment for various diseases. This study aimed to investigate the effects of individual alpha frequency tACS (IAF-tACS) on FC within the default mode network (DMN) in healthy individuals, particularly following the triple network model.

MATERIALS AND METHODS: 27 healthy participants were recruited, who underwent a 20-min IAF-tACS session over parieto-occipital areas and three magnetoencephalography (MEG) recordings: two pre-stimulation and one post-stimulation. Participants were randomly assigned to either the stimulation or sham group. Both dynamic FC (dFC) and static FC (sFC) were evaluated through the leakage corrected amplitude envelope correlation (AEC-c). Statistical analyses compared both Pre-Post FC ratio between groups through ratio t-tests and intragroup FC changes through repeated measures t-tests, with FDR correction applied to account for multiple comparisons. An additional analysis simulated the influence of the cortical folding on the effect of tACS over FC.

RESULTS: IAF-tACS significantly decreased sFC in intra- and inter-DMN links in the stimulation group compared to the sham group, with a special influence over antero-posterior links between hubs of the DMN. Negative correlations were found between AEC-c sFC changes and power alterations in posterior DMN areas, suggesting a complex interaction between cortical folding and electric field direction. On the other hand, dFC increased in both sham and stimulation groups, and no between-group differences were found.

CONCLUSION: Against our initial hypothesis, IAF-tACS reduced sFC in the DMN, possibly due to phase disparities introduced by cortical gyrification. These findings suggest that tACS might modulate FC in a more complex manner than previously thought, highlighting the need for further research into the personalized application of neuromodulation techniques, as well as its potential therapeutic implications for conditions like Alzheimer's disease.},
}

@article {pmid40438507,
year = {2025},
author = {Wang, Y and Li, Y and Zhou, L and Yuan, Y and Liu, C and Zeng, Z and Chen, Y and He, Q and Wu, Z},
title = {Identification and validation of pyroptosis-related genes in Alzheimer's disease based on multi-transcriptome and machine learning.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1568337},
pmid = {40438507},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) progression is characterized by persistent neuroinflammation, where pyroptosis-an inflammatory programmed cell death mechanism-has emerged as a key pathological contributor. However, the molecular mechanisms through which pyroptosis-related genes (PRGs) drive AD pathogenesis remain incompletely elucidated.

METHODS: We integrated multiple transcriptomes of AD patients from the GEO database and analyzed the expression of PRGs in combined datasets. Machine learning algorithms and comprehensive bioinformatics analysis (including immune infiltration and receiver operating characteristic (ROC)) were applied to identify the hub genes. Additionally, we validated the expression patterns of these key genes using the expression data from AD mice and constructed potential regulatory networks through time series and correlation analysis.

RESULTS: We identified 91 PRGs in AD using the weighted gene co-expression network analysis (WGCNA) and differentially expressed genes analysis. By application of the protein-protein interaction and machine learning algorithms, seven pyroptosis feature genes (CHMP2A, EGFR, FOXP3, HSP90B1, MDH1, METTL3, and PKN2) were identified. Crucially, MDH1 and PKN2 demonstrated superior performance in terms of immune cell infiltration, ROC curves, and experimental validation. Furthermore, we constructed the long non-coding RNA and mRNA (lncRNA-mRNA) regulatory network of these characteristic genes using the gene expression profiles from AD mice at varying ages, revealing the potential regulatory mechanism in AD.

CONCLUSION: This study provides the first comprehensive characterization of pyroptosis-related molecular signatures in AD. Seven hub genes were identified, with particular emphasis on MDH1 and PKN2. Their superior performances were validated through comprehensive bioinformatic analysis in both patient and mouse transcriptomes, as well as the experimental data. Our findings establish foundational insights into pyroptosis mechanisms in AD that may inform novel treatment strategies targeting neuroinflammatory pathways.},
}

@article {pmid40438332,
year = {2025},
author = {Yu, T and Yu, Y and Zhao, J and Li, H and Lu, H and Li, Y and Peng, Y and Wang, S and Wei, W and Cheng, X},
title = {Qifuyin alleviates anxiety and depression in 3×Tg-AD mice by modulating neuroendocrine function.},
journal = {Frontiers in psychiatry},
volume = {16},
number = {},
pages = {1554866},
pmid = {40438332},
issn = {1664-0640},
abstract = {BACKGROUND: Alzheimer's disease (AD) is frequently accompanied by behavioral and psychological symptoms of dementia (BPSD). Studies have shown that 3×Tg-AD mice, a classical animal model of AD, exhibit anxiety and depression-like behaviors characteristic of BPSD.

OBJECTIVE: This study investigated the effects of Qifuyin on anxiety and depression-like behaviors in 3×Tg-AD mice.

METHODS: The 20 male and female C57BL/6 mice at 10.3 months of age were used as the control group, while the 82 male and female 3×Tg-AD mice of the same age were divided into five groups. The control and model groups were gavaged with solvent, the positive medicine group received a combination of donepezil and memantine, and the Qifuyin (QFY) groups were divided into three doses: low, medium, and high. The effects of QFY on anxiety-like behaviors in mice were assessed using the open field test (OFT) and elevated plus maze (EPM) test, while depression-like behaviors were evaluated through the forced swim test (FST) and sucrose splash test (ST). Plasma levels of corticosterone (CORT), testosterone (T), and estradiol (E2) were measured using ELISA, while adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), corticotropin-releasing hormone (CRH), and gonadotropin-releasing hormone (GnRH) were quantified via radioimmunoassay. Differences in plasma hormone levels among groups were analyzed using principal component analysis (PCA). Pearson correlation analysis was conducted to explore the relationships between plasma hormones and behavioral phenotypes, and multiple linear regression was employed to identify the hormones most strongly correlated with anxiety and depression-like behaviors in mice following QFY treatment.

RESULTS: In 3×Tg-AD mice, anxiety-like behaviors were characterized by reduced the duration, number of visits, and total distances in central area during the OFT. The EPM revealed reduced the duration and frequency in the open arms for both sexes. Depression-like behaviors were evident in the FST, with increased immobility, and in the ST, with prolonged grooming latency in both sexes and reduced grooming frequency in females. The treatment of QFY alleviated these behaviors. In males, In the model group, plasma ACTH, GnRH, and FSH levels were significantly decreased. In the QFY-treated group, plasma CRH levels were significantly reduced, while GnRH levels were significantly increased. In the model group of females, plasma ACTH levels were significantly elevated, while FSH and LH levels were markedly reduced. In the QFY-treated group, plasma CORT levels were significantly decreased, whereas FSH and LH levels were significantly increased. Multiple linear regression indicated QFY mainly mitigates anxiety and depression-like symptoms through modulating GnRH in males and T and ACTH in females.

CONCLUSIONS: The administration of QFY alleviates anxiety and depression in 3×Tg-AD mice by regulating the HPA, HPT and HPO axes.},
}

@article {pmid40437535,
year = {2025},
author = {Bregman, N and Nathan, T and Shir, D and Omer, N and Levy, MH and David, AB and Aizenstien, O and Lotan, E and Alcalay, Y and Awad, AA and Gadoth, A and Ash, E and Shiner, T},
title = {Lecanemab in clinical practice: real-world outcomes in early Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {119},
pmid = {40437535},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Male ; Female ; Aged ; Treatment Outcome ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Magnetic Resonance Imaging ; Aged, 80 and over ; Mental Status and Dementia Tests ; Follow-Up Studies ; Amyloid beta-Peptides/metabolism ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Lecanemab, a monoclonal antibody targeting amyloid beta, has recently been approved for treatment of early-stage Alzheimer's disease (AD), demonstrating amyloid plaque reduction and slowing of cognitive decline in clinical trials. However, real-world data on its efficacy and safety remain limited. The Cognitive Neurology Unit at Tel Aviv Medical Center (TLVMC) established an infrastructure to facilitate advanced treatments for AD, utilising a multidisciplinary approach to patient screening, diagnosis, treatment initiation and follow up.

METHODS: Lecanemab administration at the TLVMC commenced in November 2023. Patients with biomarker-confirmed early-stage AD were screened via a structured referral system, including neurological evaluations, MRI, lumbar puncture or Amyloid-PET, genetic testing, and multidisciplinary team (MDT) consensus discussions. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) at baseline, six months, and twelve months. Safety monitoring included routine MRI scans for amyloid-related imaging abnormalities (ARIA).

RESULTS: Between July 2023 and January 2025, 169 patients were screened and 86 initiated lecanemab treatment. By January 2025, 53 patients had reached the 6-month follow-up date. In the intention-to-treat (ITT) population, MMSE scores declined significantly over 6 months (F(1, 45.13) = 7.41, p =.009). Subgroup analysis revealed a significant decline in younger patients (n = 31; F(1, 24.67) = 8.06, p =.009), but not in older patients (n = 22; F(1, 19.25) = 0.67, p =.424). At 12 months, 31 patients had reached follow-up, with no significant change in MMSE scores observed (F(1, 17.18) = 2.49, p =.133). Age subgroup analysis was not performed at 12 months due to limited sample size. No significant correlations were found between baseline biomarkers and cognitive change. ARIA occurred in 18.6% of patients, mostly asymptomatic. One patient experienced symptomatic ARIA, required hospitalization with intravenous treatment, and discontinued therapy. A mixed-effects model showed no significant effect of ARIA on MMSE change (p =.264) and no interaction with time (p =.433). Infusion-related reactions occurred in 22.1%, all mild and transient. Treatment was discontinued in 19.8% of patients due to ARIA, financial barriers, comorbidities, or personal preference.

CONCLUSIONS: This real-world analysis demonstrates the feasibility and safety of Lecanemab administration for early-stage AD within a tertiary hospital setting. Establishing dedicated infrastructure enabled streamlined patient evaluations and treatment. The findings suggest a differential response across age groups, consistent with clinical trial data. Continued longitudinal follow-up is needed to assess long-term efficacy and safety.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging
Male
Female
Aged
Treatment Outcome
Middle Aged
*Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects
Magnetic Resonance Imaging
Aged, 80 and over
Mental Status and Dementia Tests
Follow-Up Studies
Amyloid beta-Peptides/metabolism
Neuropsychological Tests

@article {pmid40437286,
year = {2025},
author = {Zhu, T and Shen, F and Jia, X and Zhou, H and Ni, W and Wang, S and Wu, D and Gao, H and Shang, Z and Zhou, Y and Han, J and Jin, G and Dong, F and Zu, J and Yang, X and Shi, H and Zhou, C and Hua, F},
title = {Late-Stage Activation of Toll-like receptor 3 Alleviates Cognitive Impairment and Neuropathology in an Alzheimer's Disease Mouse Model.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40437286},
issn = {1559-1182},
support = {82171420//National Nature Science Foundation of China/ ; },
abstract = {This study was to investigate the effects of Toll-like receptor-3 (TLR3) activation on cognitive impairment and neuropathology in late-stage of Alzheimer's disease in a mouse model. Amyloid protein precursor (APP)/presenilin-1 (PSEN1) (APP/PSEN1) mice were treated with Poly (I:C), a specific for TLR3. A panel of neurobehavioral tests were conducted to evaluate their cognitive functions. Aβ deposition, plasma Aβ levels, neuropathological changes, and activation of TLR3- TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling were assessed by magnetic resonance imaging (MRI), electrophysiological recordings, transmission electron microscopy, Western blotting, immunofluorescence staining, and qPCR. The data demonstrated that Poly (I:C) significantly attenuated cognitive and neuropathological impairments, compared with APP/PSEN1 mice without Poly (I:C) treatment. Administration of Poly (I:C) significantly reduced brain Aβ1-42 deposition and the levels of Aβ1-40 and Aβ1-42 in peripheral blood. In addition, treatment with Poly (I:C) significantly up-regulated the expression of anti-inflammatory factors and inhibited the expression of pro-inflammatory factors. The data indicated that systemic application of TLR3 agonist Poly(I:C) attenuated the brain damage, improved the cognitive function, and reduced the levels of Aβ1-42 in brain and peripheral blood. The underlying mechanism might attribute to the up-regulation of p-IRF3 that increases the expression of anti-inflammatory factors and the inhibition of p-NF-κB that reduces the expression of pro-inflammatory factors.},
}

@article {pmid40437285,
year = {2025},
author = {Verma, V and Rao, L and Chaudhary, M and Jain, S and Pinapati, KK and Dey, A and Sharma, S and Srivastava, N},
title = {Spirilloxanthin from Verbesina encelioides Flower Extract has Neuroprotective Benefits in Scopolamine-Induced Memory Impaired Rats that Resemble Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40437285},
issn = {1559-1182},
abstract = {Neuronal degeneration is a widespread complication associated with ageing, with Alzheimer's disease (AD) being one of the most prevalent neurodegenerative disorders. AD is marked by limited treatment options and significant side effects, prompting growing interest in natural compounds for their therapeutic potential. This study evaluates the neuroprotective effects of spirilloxanthin, a major bioactive compound identified in the flower extract of Verbesina encelioides (VFE), against scopolamine-induced neurobehavioral impairments in a rat model of AD. Gas chromatography-mass spectrometry (GC-MS) analysis confirmed spirilloxanthin as a key constituent of the extract. The administration of purified VFE to rats exhibiting AD-like symptoms significantly improved learning and memory. Biochemical analyses further revealed enhanced cognitive performance and a notable reduction in free radical production, indicating mitigation of oxidative stress. Complementary in silico molecular docking studies were performed to examine the interactions between spirilloxanthin and gingkolide A with acetylcholinesterase, shedding light on their potential mechanisms of action. In summary, the study demonstrates that VFE improves cognitive function and counteracts scopolamine-induced deficits, highlighting V. encelioides as a promising natural therapeutic candidate for neurodegenerative conditions such as dementia and Alzheimer's disease.},
}

@article {pmid40437281,
year = {2025},
author = {Jiang, H and Zhao, T and He, C and Liu, B and Ai, W and Chen, Y and Moriyama, H},
title = {Effects of electrical muscle stimulation on cognitive function and neuropathology in senescence-accelerated mouse (SAMP8) model of aging-associated cognitive decline.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {40437281},
issn = {2509-2723},
abstract = {The global increase in aging populations has heightened the urgency to develop effective interventions for age-related cognitive decline. Skeletal muscle has recently emerged as a potential modulator of brain health, particularly in the context of aging. This study investigates the effects of electrical muscle stimulation (EMS) on cognitive function and neuropathology in Senescence-Accelerated Mouse (SAMP8), a model of aging-associated cognitive decline. SAMP8 mice were divided into 3 groups: healthy controls (SAMR1), untreated SAMP8, and EMS-treated SAMP8. EMS was applied daily for 30 days, and behavioral, histological, and molecular markers were analyzed. Results demonstrated that EMS significantly improved muscle strength and endurance while reducing amyloid-β accumulation and phosphorylated tau (p-Tau) levels in the hippocampus. Furthermore, EMS decreased neuroinflammation and partially restored synaptic plasticity. However, EMS had limited effects on cortical pathology and cognitive function, suggesting that localized brain changes may not fully translate to behavioral improvements. These findings indicate that EMS exerts neuroprotective effects through skeletal muscle activation, providing a potential non-pharmacological intervention for age-related neurodegeneration. Future studies should explore the underlying mechanisms and translational applicability to human dementia treatment.},
}

@article {pmid40436763,
year = {2025},
author = {Omura, T and Usui, C and Matsushima-Nishiwaki, R and Kozawa, O and Tokuda, H},
title = {The distinct effect between Amyloid β (1‒40) and Amyloid β (1‒42) on the TRAP-stimulated platelet activation in diabetes mellitus.},
journal = {Biomedical research (Tokyo, Japan)},
volume = {46},
number = {3},
pages = {119-128},
doi = {10.2220/biomedres.46.119},
pmid = {40436763},
issn = {1880-313X},
mesh = {Humans ; *Amyloid beta-Peptides/pharmacology/metabolism ; *Platelet Activation/drug effects ; Male ; Female ; *Peptide Fragments/pharmacology/metabolism ; Middle Aged ; *Diabetes Mellitus/metabolism/blood ; Phosphorylation/drug effects ; Platelet Aggregation/drug effects ; Aged ; p38 Mitogen-Activated Protein Kinases/metabolism ; Blood Platelets/metabolism/drug effects ; Adult ; },
abstract = {Amyloid β (Aβ) (1‒40) is the major form in amyloid plaques, while Aβ (1‒42) is predominant in neuronal plaques. Anti-Aβ antibodies are clinically accepted for Alzheimer's disease treatment to remove Aβ from neuronal plaques; however, increase of intracranial hemorrhagic risk is a major concern. We reported that Aβ (1‒40) inhibits thrombin receptor-activating protein (TRAP)-induced platelet activation in healthy volunteers, and the responsiveness of Aβ (1‒40) to the platelet activation is related to brain atrophy in diabetes mellitus (DM) patients. We investigated the difference between the effects of Aβ (1‒40) and Aβ (1‒42) on the platelet activation in DM participants. Both isoforms suppressed the platelet aggregation, but the effect of Aβ (1‒42) was smaller than Aβ (1‒40). The effect of Aβ (1‒42) on the TRAP-stimulated phosphorylation of p38 mitogen-activated protein kinase and stress-activated protein kinase/c-Jun N-terminal kinase was smaller than Aβ (1‒40). Although the differences were not clarified, the effective ratio of Aβ (1‒40) to Aβ (1‒42) on the PDGF-AB secretion effect was related to the ratio on the aggregation and the phosphorylated-HSP27 secretion. These results suggest that the difference of the effects exists between Aβ (1‒40) and Aβ (1‒42) on the TRAP-stimulated platelet activation individually in the DM patients.},
}

Humans
*Amyloid beta-Peptides/pharmacology/metabolism
*Platelet Activation/drug effects
Male
Female
*Peptide Fragments/pharmacology/metabolism
Middle Aged
*Diabetes Mellitus/metabolism/blood
Phosphorylation/drug effects
Platelet Aggregation/drug effects
Aged
p38 Mitogen-Activated Protein Kinases/metabolism
Blood Platelets/metabolism/drug effects
Adult

@article {pmid40436365,
year = {2025},
author = {Bhattacharjee, B and Shakya, A and Shivavedi, N and Sahu, RK and Sandhanam, K},
title = {Exploring the combined neuroprotective effects of resveratrol and hesperidin in a scopolamine-induced rat model of cognitive impairment.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.05.302},
pmid = {40436365},
issn = {1873-7544},
abstract = {The occurrence of cognitive impairment in normal aging and sporadic Alzheimer's disease is linked to oxidative stress. Resveratrol, a polyphenolic molecule, and hesperidin, a flavanone glycoside have exhibited powerful anti-oxidant and neuroprotective effects. The present study was designed to explore the neurotherapeutic potential of combination between resveratrol and hesperidin as preventative herbal remedies to inhibit oxidative stress and cholinergic and mitochondrial dysfunction in scopolamine-induced cognitive impairments in rats. Resveratrol (20 mg/kg, p.o.), hesperidin (20 mg/kg, p.o.), and its combination were administered orally up to 21 days. Cognitive impairment was induced by intraperitoneal injection of scopolamine (1 mg/kg, i.p.) to rats for 5 days (15th, 16th, 17th, 18th, and 19th). Learning and memory function in rats were appraised by using the Morris water maze. Subsequently, the content of oxidative-nitrosative stress parameters, the activity of acetylcholinesterase (AChE), electron transport chain complexes, brain-derived neurotrophic factor (BDNF), and pro-inflammatory cytokines mediators (TNF-α and IL-6) in hippocampus brain areas of rats were measured. Scopolamine treatment significantly produced learning and memory impairment, oxidative-nitrosative stress, cholinergic dysfunction, mitochondrial deficit, reduced BDNF, and increased TNF-α and IL-6 levels. Whereas, resveratrol and hesperidin combination therapy effectively improved brain anti-oxidant status, lowered brain mitochondrial impairments, and neuro-inflammation in rats as compared to mono-therapy. Our findings demonstrated that the resveratrol and hesperidin combination group showed excellent anti-cognitive impairment properties compared to single therapy. The combination therapy exhibited a favorable effect in suppressing scopolamine-induced cognitive impairment, either additively, synergistically, or through distinct molecular pathways.},
}

@article {pmid40436233,
year = {2025},
author = {Chavez-López, LM and Silvestre-Martínez, JH and Del Carmen Lugo-Ibarra, K and Castro-Ceseña, AB},
title = {A comprehensive approach to Alzheimer's Disease: Exploring Nanotechnology, treatment Innovations, and sex differences.},
journal = {Brain research},
volume = {},
number = {},
pages = {149718},
doi = {10.1016/j.brainres.2025.149718},
pmid = {40436233},
issn = {1872-6240},
abstract = {In the world, over 50 million people are living with Alzheimer's disease (AD), and in thirty years, this number is expected to double or even exceed that. AD is a form of dementia characterized by memory loss, language difficulties, and impaired thinking skills. It involves the accumulation of beta-amyloid plaques and tau tangles in the brain, leading to neurodegeneration and disrupted neuron communication. After diagnosis, patients typically survive for four to eight years, though some may live up to 20 years. Currently, there is no cure, and the available treatment options are limited in improving the quality of patients' lives. However, a promising perspective for treatment based on nanotechnology narrows down the possibility of personalized treatment. In this review, we explore several topics related to Alzheimer's disease to provide a comprehensive understanding of how nanotechnology can enhance treatment approaches. We examine various types of nano treatments and delivery methods, as well as the challenges they face and their associated benefits. Additionally, we highlight current nano treatments in development and discuss improved cell and animal models that can effectively test these treatments for patient safety. We also address sex differences in the pathophysiology of Alzheimer's disease, which may allow for more targeted treatment strategies. By considering these factors in conjunction, we move closer to realizing personalized medicine, ultimately improving the quality of life for patients. Nano treatments offer the potential for more specific, safer, and effective solutions in managing Alzheimer's disease.},
}

@article {pmid40435316,
year = {2025},
author = {Abdel-Haleem, AM and Casavant, E and Toth, B and Teng, E and Monteiro, C and Pandya, NJ and Glock, C and Hoogenraad, CC and Friedman, BA and Yeh, FL and Anania, VG and Novikova, G},
title = {CSF proteomics of semorinemab Alzheimer's disease trials identifies cell-type specific signatures.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf200},
pmid = {40435316},
issn = {1460-2156},
abstract = {Targeting of tau pathology has long been proposed as a potential therapeutic strategy for Alzheimer's disease (AD). Semorinemab is a humanized IgG4 monoclonal antibody that binds to all known isoforms of full-length tau with high affinity and specificity. Semorinemab's safety and efficacy have been studied in two Phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trials: Tauriel (prodromal-to-mild AD; NCT03289143; in which semorinemab failed to demonstrate clinical efficacy) and Lauriet (mild-to-moderate AD; NCT03828747. However, semorinemab was associated with a significant slowing in progression in a co-primary endpoint of cognition only in Lauriet but not in Tauriel. Proteomic profiling of CSF collected in these trials was performed to gain a better understanding of the effect of semorinemab in light of the different clinical outcomes. CSF was collected from a subset of patients at baseline and after 49 or 73 weeks in Tauriel and baseline and after 49 or 61 weeks in Lauriet. Samples were analyzed using single-shot FAIMS-DIA-MS and analyzed with Spectronaut and MS Stats. Proteomics results were integrated with publicly available single-nucleus brain datasets to contextualize cellular expression profiles of differentially expressed proteins. A novel proteomics dataset was generated using more than 250 cerebrospinal fluid (CSF) samples where more than 3500 proteins were detected. Treatment-associated proteomic signatures were defined for each clinical trial as the set of proteins significantly elevated in the treatment arm in the respective trial. Integration of the corresponding gene signatures with brain single-nucleus RNA-seq datasets from AD and healthy age-matched controls revealed that the Lauriet signature genes were enriched in microglia, while Tauriel signature genes were more broadly expressed across brain cell types. Furthermore, the Lauriet gene signature was significantly upregulated in microglia from AD patients compared to non-demented controls. The elevation of proteins such as CHI3L1 and GPNMB with treatment suggested an activated glial state. This study demonstrates the utility of CSF clinical proteomics to assess the pharmacodynamic response of semorinemab and contributes to our understanding of how an anti-tau antibody influences disease-relevant pathophysiology in AD.},
}

@article {pmid40434641,
year = {2025},
author = {Tian, L and Long, G and Zhu, S and Wang, Y and Xu, P and Liu, L and Yao, H and Fang, S and Chen, S and Li, S},
title = {Nanoimmunomodulation of the Aβ-STING feedback machinery in microglia for Alzheimer's disease treatment.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {22},
pages = {e2427257122},
doi = {10.1073/pnas.2427257122},
pmid = {40434641},
issn = {1091-6490},
support = {2024YFA1212300//National Key R&D Program of China/ ; 82373224//Natonal Natural Science Foundation of China/ ; SKLNMZZ2024JS28//Jiangsu Specially Appointed Professor Program, Project of the State Key Laboratory of Natural Medicines/ ; 2023ZD22//Key Project of the Natural Science Foundation of Inner Mongolia/ ; },
mesh = {*Alzheimer Disease/immunology/metabolism/therapy/drug therapy/pathology ; *Microglia/metabolism/immunology/drug effects ; Animals ; *Amyloid beta-Peptides/metabolism/immunology ; Mice ; *Membrane Proteins/metabolism/antagonists & inhibitors/immunology ; Humans ; Signal Transduction ; Blood-Brain Barrier/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Feedback, Physiological ; Mice, Inbred C57BL ; },
abstract = {Imbalanced production and clearance of amyloid-β (Aβ) is a hallmark pathological feature of Alzheimer's disease (AD). While several monoclonal antibodies targeting Aβ have shown reductions in amyloid burden, their impact on cognitive function remains controversial, with the added risk of inflammatory side effects. Dysregulated stimulator of interferon genes (STING) signaling is implicated in neurodegenerative disorders, yet the biological interaction between this pathway and Aβ, as well as their combined influence on AD progression, is poorly understood. Here, we show that while microglia play a protective role in clearing extracellular Aβ, excessive Aβ engulfment triggers the cytosolic leakage of mitochondrial DNA for cGAS-STING cascade. This creates a negative feedback loop that not only exacerbates neuroinflammation but also impairs further Aβ clearance. To address this, we present a nanomedicine approach termed "Aβ-STING Synergistic ImmunoSilencing Therapy (ASSIST)". ASSIST comprises STING inhibitors encapsulated within a blood-brain barrier (BBB)-permeable polymeric micelle that also serves as an Aβ scavenger. Through a multivalent interaction mechanism, ASSIST efficiently destabilizes Aβ plaques and prevents monomer aggregation, subsequently promoting the engulfment of the dissociated Aβ by microglia rather than neurocytes. Furthermore, the STING signaling induced by excessive Aβ uptake is blocked, reducing inflammation and restoring microglial homeostatic functions involved in Aβ clearance. Intravenous administration of ASSIST significantly reduces Aβ burden and improves cognition in AD mice, with minimal cerebral amyloid angiopathy or microhemorrhages. We provide a proof-of-concept nanoengineering strategy to target the maladaptive immune feedback loop arising from conventional immunotherapy for AD treatment.},
}

*Alzheimer Disease/immunology/metabolism/therapy/drug therapy/pathology
*Microglia/metabolism/immunology/drug effects
Animals
*Amyloid beta-Peptides/metabolism/immunology
Mice
*Membrane Proteins/metabolism/antagonists & inhibitors/immunology
Humans
Signal Transduction
Blood-Brain Barrier/metabolism
Mice, Transgenic
Disease Models, Animal
Feedback, Physiological
Mice, Inbred C57BL

@article {pmid40434374,
year = {2025},
author = {Chan, JW and Corradetti, G and Wu, X and Astraea, N and Arakaki, X and Fonteh, AN and Suchy-Dicey, AM and Sadda, S},
title = {Perifoveal Choriocapillaris Flow Deficits Associated With Cerebrospinal Fluid Aβ42/tau in Presymptomatic Alzheimer's Disease.},
journal = {Translational vision science & technology},
volume = {14},
number = {5},
pages = {27},
doi = {10.1167/tvst.14.5.27},
pmid = {40434374},
issn = {2164-2591},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/physiopathology/diagnostic imaging ; *Amyloid beta-Peptides/cerebrospinal fluid ; Male ; *tau Proteins/cerebrospinal fluid ; Female ; Aged ; Middle Aged ; *Peptide Fragments/cerebrospinal fluid ; *Choroid/blood supply/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; Tomography, Optical Coherence/methods ; },
abstract = {PURPOSE: This study investigated the association between swept-source OCTA (SS-OCTA) choriocapillaris flow deficit percentage (CC FD%) and cerebrospinal fluid (CSF) biomarkers in presymptomatic Alzheimer's disease (AD).

METHODS: Twenty-three cognitively healthy (CH) participants, including those with pathological (CH-PAT) and normal (CH-NAT) Aβ42/tau ratios, underwent lumbar puncture for CSF Aβ42/tau and ptau-181 quantification using electrochemiluminescence assays. OCTA en face images of the choriocapillaris were analyzed for flow deficits within a 6 × 6 mm macular grid and 3- and 6-mm Early Treatment of Diabetic Retinopathy Study (ETDRS) perifoveal rings. The association between CC FD% and CSF Aβ42/tau and CSF ptau-181 levels was evaluated.

RESULTS: Perifoveal microvascular changes in the choriocapillaris outer ring (6-mm ETDRS ring) were significantly correlated with the CSF Aβ42/tau ratio in CH-PATs compared to CH-NATs. However, linear regression analysis across all CH participants (CH-PAT + CH-NAT) revealed that only age was significantly associated with CSF ptau-181 levels.

CONCLUSIONS: Our findings suggest that this cohort is in an early preclinical AD stage, without ptau-181 biomarker evidence of established AD. SS-OCTA measures may complement CSF A/T (amyloid/tau) levels, helping to define transitional stages from CH-NAT to CH-PAT during presymptomatic AD.

TRANSLATIONAL RELEVANCE: By identifying the transition from normal aging to presymptomatic AD, SS-OCTA metrics combined with biofluid markers could enhance AD oculomics by stratifying disease risk and prioritizing treatment interventions.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/physiopathology/diagnostic imaging
*Amyloid beta-Peptides/cerebrospinal fluid
Male
*tau Proteins/cerebrospinal fluid
Female
Aged
Middle Aged
*Peptide Fragments/cerebrospinal fluid
*Choroid/blood supply/diagnostic imaging
Biomarkers/cerebrospinal fluid
Tomography, Optical Coherence/methods