@article {pmid41308015,
year = {2025},
author = {Usher, MR and Aybar-Torres, AA and Jin, L},
title = {Identification of common human TMEM173 genotypes associated with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251396973},
doi = {10.1177/13872877251396973},
pmid = {41308015},
issn = {1875-8908},
abstract = {BackgroundRecent animal studies have revealed STING (Stimulator of interferon genes) as a potential key player in Alzheimer's disease (AD). The actual impact of human STING on AD, however, is unknown. Mouse STING studies were done in WT/WT. However, TMEM173, the human gene encodes STING, has 5 common, distinct, sometimes opposite functional alleles that result in 25 TMEM173 genotypes. Only ∼50% of whites, 36% of African Americans (AA), 22% of East Asians are WT/WT. Past STING cancer immunotherapy clinic trials, which did not consider human TMEM173 heterogeneity, all failed.Objective(1) Discover new protective and risk AD genetic factors across populations or AA-specific. (2) Establish the physiological significance of common human TMEM173 genotypes and human diseases.MethodsWe conduct a large-scale (∼15,000 individuals) case-control analysis between TMEM173 genotypes and AD using data from The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site. The data include late-onset AD (LOAD) non-Hispanic White (NHW), early-onset AD (EOAD) NHW, and AA.ResultsA common H232/HAQ TMEM173 genotype is associated with AD protection across the populations. An AA-specific TMEM173 genotype H232/Q293 increases the risk for AA males (OR = 17.7148), especially in the APOE ε3/ε3 population.ConclusionsThe findings discovered the first AA-specific high AD risk factor and established an association between human TMEM173 and AD, paving the way for STING-targeting effective AD healthcare.},
}

@article {pmid41308013,
year = {2025},
author = {Zhu, X and Zhang, L and Qin, C},
title = {Hub genes and diagnostic model associated with mitochondrial function in Alzheimer's disease.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.70104},
pmid = {41308013},
issn = {2576-2095},
support = {2023-PT180-01//Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences/ ; 2023-PT330-01//Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences/ ; 2021-I2M-1-034//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 82161138027//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder, with mitochondrial dysfunction being observed in both AD patients and mouse models. Nonetheless, further investigation is required to elucidate the pathogenic genes associated with AD and to develop early diagnostic methodologies centered on mitochondrial function.

METHODS: In this study, the dataset GSE132903 was retrieved from the GEO database, encompassing both non-demented (ND) control and AD samples. Through the combination of differential expression gene analysis, weighted gene co-expression network analysis, and intersection with mitochondrial database gene sets, four hub genes associated with AD were identified. These four hub genes were subsequently validated in APP/PS1 and 5xFAD mouse models using molecular biology techniques.

RESULTS: The hub genes identified through bioinformatics analysis include SYNJ2BP, VDAC1, NUBPL, and COX19. Within the GSE132903 dataset, the expression levels of SYNJ2BP, NUBPL, and COX19 were significantly elevated in the AD group compared to the non-demented (ND) group, whereas VDAC1 expression was reduced in the AD group relative to the ND group. Furthermore, in the hippocampus of APP/PS1 and 5xFAD mouse models, the expression patterns of SYNJ2BP and NUBPL were consistent with the bioinformatics analysis results.

CONCLUSION: Hub genes identified here through bioinformatics and molecular biology may help early diagnosis of AD patients and may also help build new AD models to explore its pathogenesis.},
}

@article {pmid41307999,
year = {2025},
author = {Tsai, AP and Henze, DE and Ramirez Lopez, E and Haberberger, J and Dong, C and Lu, N and Atkins, M and Costa, EK and Farinas, A and Oh, HS and Moran-Losada, P and Le Guen, Y and Isakova, A and Quake, SR and Wyss-Coray, T},
title = {Spatial and single-cell transcriptomics reveal the reorganization of cerebellar microglia with aging.},
journal = {Cell reports},
volume = {44},
number = {12},
pages = {116624},
doi = {10.1016/j.celrep.2025.116624},
pmid = {41307999},
issn = {2211-1247},
abstract = {The cerebellum, essential for motor coordination and increasingly recognized for its role in cognition, is typically considered more resilient to aging and largely spared from hallmark Alzheimer's disease (AD) pathology. However, transcriptomic analyses across fifteen mouse brain regions revealed that the cerebellum undergoes some of the earliest and most pronounced age-related changes. To investigate cerebellar aging, we applied single-nucleus RNA sequencing (RNA-seq), microglial bulk RNA-seq, and multiplexed error-robust fluorescence in situ hybridization (MERFISH)-based spatial transcriptomics. Microglia showed the most prominent changes, including elevated expression of a neuroprotective signature and reduced expression of a lipid-droplet-accumulating signature compared to hippocampal microglia. Spatial analyses further revealed that aged cerebellar microglia were positioned in close proximity to granule cells. Utilizing this relationship, we identified a proximity-dependent transcriptional state defined by the neuron-associated microglial signature. This signature reveals a region-specific microglial adaptation, highlighting cerebellar reorganization with age and potential resilience to AD.},
}

@article {pmid41307953,
year = {2025},
author = {Gong, Z and Laporte, JP and Guo, AY and Bilgel, M and Bae, J and Fox, NY and de Rouen, A and Zhang, N and Taranath, A and de Cabo, R and Egan, JM and Ferrucci, L and Bouhrara, M},
title = {Early axonal degeneration linked to clinical decline in Alzheimer's disease progression revealed with diffusion MRI.},
journal = {The Journal of clinical investigation},
volume = {},
number = {},
pages = {},
doi = {10.1172/JCI196638},
pmid = {41307953},
issn = {1558-8238},
abstract = {BACKGROUND: Axonal degeneration is believed to be an early hallmark of Alzheimer's disease (AD). This study investigated the temporal trajectory of axonal loss and its association with cognitive and functional decline using diffusion MRI-derived Axonal Density Index (dMRI-ADI).

METHODS: Longitudinal dMRI, CSF and PET data from the ADNI were analyzed, including 117 cognitively normal (CN) and 88 impaired (CI) subjects, consisting of 74 mild cognitive impairment (MCI) and 14 AD individuals. Linear mixed-effects models examined group differences as well as associations between baseline and longitudinal changes in ADI, CSF or PET biomarkers and clinical outcomes. Results derived from larger CSF (n=527) and PET (tau-PET: n=870; amyloid-PET: n=1581) data were also presented.

RESULTS: Compared to CN, the CI group exhibited significantly lower baseline ADI values and steeper longitudinal decline (p<10-⁶). Lower baseline ADI predicted faster cognitive and functional decline in the CI group (MMSE: p=0.03; CDR-SB: p<10-⁴), and longitudinal decreases in ADI were associated with worsening clinical outcomes (MMSE: p=0.001; CDR-SB: p<10-¹²). Compared to CSF and PET biomarkers, ADI demonstrated superior sensitivity in tracking disease progression and matched these biomarkers in predicting future cognitive and functional decline. Furthermore, decreases in ADI were significantly associated with declines in clinical outcomes; an association observed only with amyloid-PET, but not CSF biomarkers.

CONCLUSION: Axonal degeneration is an early and clinically meaningful feature of AD. ADI is a promising noninvasive biomarker for early detection, prognosis, and disease monitoring.

CLINICALTRIALS: gov NCT00106899.

FUNDING: This work was supported by the National Institute on Aging IRP.},
}

@article {pmid41307609,
year = {2025},
author = {Katayama, S and Tsujimoto, M and Suzuki, K and Ueda, K and Shimoura, K and Suo, S and Hatakeyama, N},
title = {Care Partners' Perceptions of Amyloid-Targeting Therapy and Treat‑to‑Clearance for Alzheimer's Disease in Japan: A Qualitative Study.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {41307609},
issn = {2193-8253},
abstract = {INTRODUCTION: Donanemab has been developed as an amyloid-targeting therapy (ATT) for mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD). In registration trials involving donanemab, a treat‑to‑clearance approach was used, in which patients discontinued ATT when amyloid plaque levels decreased below a predefined threshold, which differs from previously available symptomatic treatments for AD. Our study explored care partners' perceptions regarding ATT and treat‑to‑clearance.

METHODS: This was a cross-sectional, qualitative interview study. Care partners of individuals with MCI or mild dementia due to AD participated in online semi-structured interviews about their perceptions regarding the impact of MCI or mild dementia diagnoses due to AD, the burden of supporting, and use/cessation of ATT. The qualitative data from the interviews were analyzed using a thematic approach.

RESULTS: The participants were 22 care partners (5 male/17 female), and their median age was 59 (range 35-81) years. The most common relationships between care partners and the individuals with AD were child (50.0%) and spouse/partner (45.5%); 68.2% of the care partners lived with the individuals with AD. Thematic analysis identified three major classifications (Thoughts regarding therapy; Treat‑to‑clearance; and Burdens of support), along with 15 themes and five sub-themes. Care partners expressed experiencing mental burden and time constraints, while treat‑to‑clearance could save care partners' time by reducing hospital waiting time and alleviating financial burden. Confirming the clearance of amyloid β plaques provided care partners with a sense of relief, while they remained concerned about the potential progression of AD symptoms and sought follow-up care after stopping treatment.

CONCLUSIONS: These results suggest that providing clear explanations and facilitating shared decision-making when introducing ATT, as well as introducing follow-up care and long-term evidence after stopping treatment, are needed.},
}

@article {pmid41307506,
year = {2025},
author = {Fishman, A and Grinin, P and Riljak, V},
title = {The (un-)Social Brain in Isolation.},
journal = {Physiological research},
volume = {74},
number = {5},
pages = {711-727},
pmid = {41307506},
issn = {1802-9973},
mesh = {Humans ; *Social Isolation/psychology ; *Brain/physiology/physiopathology ; Animals ; *COVID-19/psychology ; *Social Behavior ; *Stress, Psychological/psychology ; },
abstract = {The Social Brain is a distributed network of neuroanatomical regions and neurochemical systems that underpins the human capacity for social cognition, empathy, and interpersonal behavior. Social isolation (SI), defined as the objective reduction in social interaction, poses a significant threat to the integrity of this system. In this review, we synthesize evidence from human and animal studies to elucidate the biological, cognitive, and behavioral consequences of SI on the social brain. We describe how SI acts as a chronic stressor, disrupting structural connectivity, and altering neurotransmitter systems critical for social cognition. These disruptions manifest in altered social behavior, mentalization processes, and emotional reactivity, significantly contributing to increased vulnerability to psychiatric and neurodegenerative disorders, including depression, schizophrenia, substance use disorders, and Alzheimer's disease. Converging findings from studies of evolutionarily conserved mechanisms in rodent and primate models demonstrate that SI compromises neurodevelopment, attenuates neuroplasticity, and triggers maladaptive stress responses, highlighting that social deprivation has profound neurobiological and behavioral consequences that greatly overlap with the pathophysiological changes seen in neuropsychiatric disorders. Furthermore, we explore the role of indirect stressors resulting from SI such as touch deprivation and digital-era social disconnection as contemporary amplifiers of SI's neurobiological impact. In light of public health challenges such as the COVID-19 pandemic, we propose that SI should be recognized not only as a psychosocial condition but as a modifiable risk factor with transdiagnostic significance across psychiatry, neurology, and preventive medicine. Addressing SI through targeted interventions and policy measures is essential for promoting mental resilience and well-being. Key words Chronic Stress " Loneliness " Social Cognition " Socialization " Social Stress.},
}

Humans
*Social Isolation/psychology
*Brain/physiology/physiopathology
Animals
*COVID-19/psychology
*Social Behavior
*Stress, Psychological/psychology

@article {pmid41307478,
year = {2025},
author = {Wang, X and Chen, L and Qiu, J and Wang, K and Xi, P and Cheng, X and He, Z and Jiang, H},
title = {Dipeptidyl Peptidase 4 Mediated Caspase-8 Affects Cognitive Impairment in Mice With Alzheimer's Disease.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {39},
number = {23},
pages = {e71264},
doi = {10.1096/fj.202501322RR},
pmid = {41307478},
issn = {1530-6860},
support = {82204837//MOST | NSFC | National Natural Science Foundation of China-Zhejiang Joint Fund for the Integration of Industrialization and Informatization (NSFC-Zhejiang Joint Fund)/ ; 81760207//MOST | NSFC | National Natural Science Foundation of China-Zhejiang Joint Fund for the Integration of Industrialization and Informatization (NSFC-Zhejiang Joint Fund)/ ; LQ23H290004//Zhejiang Provincial Natural Science Foundation of China/ ; 2024AY10021//Jiaxing Science and Technology Plan Project‌/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism ; Male ; Mice ; *Dipeptidyl Peptidase 4/metabolism/genetics ; Mice, Inbred C57BL ; *Caspase 8/metabolism/genetics ; *Cognitive Dysfunction/metabolism ; Mice, Knockout ; Amyloid beta-Peptides/toxicity ; Disease Models, Animal ; Pyroptosis ; Dipeptidyl-Peptidase IV Inhibitors/pharmacology ; Maze Learning ; Hippocampus/metabolism ; Neurons/metabolism ; },
abstract = {To investigate the effect of dipeptidyl peptidase 4 (DPP4) on cognitive impairment in Alzheimer's disease (AD), the present study used seven-week-old male C57BL/6J and DPP4 knockout mice. The AD model was induced by microinjection of Aβ25-35 into the lateral ventricle. Morris water maze test showed that DPP4 knockout significantly improved the spatial learning and memory abilities of AD mice. Western blot results showed that DPP4 knockout increased the expression levels of BDNF, CREB and Bcl-2 in the hippocampus of AD mice while the expression levels of Caspase-8, pyroptosis-related proteins NLRP3, Caspase-1, GSDMD, IL-118, IL-1β, and apoptosis-related proteins Caspase-3 and Bax were decreased. Similar results were observed after HT22 neurons were treated with Aβ25-35 and the DPP4 inhibitor sitagliptin (Sit). Moreover, the treatment with a Caspase-8 inhibitor (Z-LETD-FMK) showed that the inhibition of Caspase-8 inhibited the expression of NLRP3 and Caspase-1 in the AD model cells, but had no further inhibitory effect under the treatment of Sit. Our results suggest that DPP4 knockout may ameliorate learning and memory dysfunction in AD model mice by regulating pyroptosis and apoptosis pathways through Caspase-8.},
}

Animals
*Alzheimer Disease/metabolism
Male
Mice
*Dipeptidyl Peptidase 4/metabolism/genetics
Mice, Inbred C57BL
*Caspase 8/metabolism/genetics
*Cognitive Dysfunction/metabolism
Mice, Knockout
Amyloid beta-Peptides/toxicity
Disease Models, Animal
Pyroptosis
Dipeptidyl-Peptidase IV Inhibitors/pharmacology
Maze Learning
Hippocampus/metabolism
Neurons/metabolism

@article {pmid41307432,
year = {2025},
author = {Nemr, MTM and Elshaier, YAAM and Ewieda, SY and Abdelaziz, MA},
title = {Pharmaceutical applications of cyclopropyl containing scaffolds: a review on recent updates.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/17568919.2025.2594969},
pmid = {41307432},
issn = {1756-8927},
abstract = {Carbocycles have been widely employed in the development of pharmaceutically active scaffolds. Cyclopropane has attracted significant attention from researchers due to its unique chemical properties among carbocycles. Subsequently, this review will focus on cyclopropane-containing pharmaceutical drug products that have been approved by the FDA (Food and Drug Administration) and are used to treat a wide variety of medical conditions. In addition to the synthesis of the cyclopropyl moiety through various chemical reactions, such as the Corey-Chaykovsky reaction and the Simmons-Smith reaction. Several cyclopropane-containing pharmaceutical drugs have been reported to exert significant anti-coagulant effects. Additionally, they also exhibit inhibitory activity against MET, a receptor tyrosine kinase, as well as vascular endothelial growth factor receptor 2 (VEGFR-2). Moreover, they showed cytotoxicity by inhibiting epidermal growth factor receptor (EGFR[L858R/T790M]). In addition to antidiabetic, anti-Alzheimer, antimalarial, antimicrobial, anti-convulsant and anti-depressant activities. Herein, we present the pharmaceutical applications of cyclopropane-containing derivatives, shedding light on the structure-activity relationship (SAR), along with some commonly reported methods for their synthesis.},
}

@article {pmid41307255,
year = {2025},
author = {Hu, H and Li, H and Chen, Y and Zhou, J and Chen, J and Tang, Q and Chen, X and Jiang, J and Sun, M and Jia, D and Xie, W and Long, C and Yang, L},
title = {Molecular pathways underlying amyloid precursor protein-mediated regulation of adult-born neurons.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00175},
pmid = {41307255},
issn = {1673-5374},
abstract = {Cleavage of amyloid precursor protein (APP) produces toxic amyloid-beta peptides, which play a critical role in the pathogenesis of Alzheimer's disease. Neuronal loss is a key feature of Alzheimer's disease. Despite the importance of APP in the proliferation of neural progenitors and the survival of adult-born granule cells in the dentate gyrus, little is known about the effect of APP deficiency on neuronal electrophysiological activities and the survival of newly born neurons. Utilizing whole-cell patch-clamp recording in combination with retroviral labeling and immunofluorescent staining in Alzheimer's disease model mice with App knockout (App-/-), we show that APP deficiency increased the number of adult-born granule cells at 4 weeks post-injection, but did not affect their intrinsic excitability or miniature current activity. In contrast, at 10 weeks post-injection, adult-born granule cells showed increased abundance and intrinsic excitability that were associated with abnormal dendritic morphology, increased miniature excitatory- and inhibitory-synaptic transmission, and decreased potassium-chloride-cotransporter 2 expression. Compared with adult-born granule cells at 10 week post-injection, mature granule cells exhibited decreased intrinsic excitability and potassium-chloride-cotransporter 2 expression alongside increased apoptosis in App-/- mice. Additionally, although App-/-mice showed abnormal freezing behavior and elevated mature granule cell activation during contextual fear conditioning, adult-born granule cells were not recruited in either App-/- or wild-type control mice. Taken together, these findings suggest that APP is required for adult-born granule cell maturation and that APP deficiency induces excitotoxicity in adult-born granule cells at 10 weeks post-injection, promoting subsequent apoptosis of mature granule cells.},
}

@article {pmid41307250,
year = {2025},
author = {Saieva, S and Scaduto, P and Fracassi, A and Guptarak, J and Zhang, WR and Johnson, K and Jupiter, DC and Marcatti, M and Zolochevska, O and Taglialatela, G and Micci, MA},
title = {Hippocampal neural stem cell-derived extracellular vesicles modulate microglia to promote resilience against tau oligomers.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00195},
pmid = {41307250},
issn = {1673-5374},
abstract = {Neural stem cells and adult hippocampal neurogenesis modulate synaptic plasticity and cognitive function. Neural stem cells secrete extracellular vesicles - microvesicles carrying biomolecular cargos - that modulate the function of other cells and contribute to homeostasis and plasticity in the central nervous system. Alzheimer's disease is marked by a reduction of neural stem cells in the hippocampus dentate gyrus. While increased neural stem cells often correlate with better learning and memory, neurogenesis alone does not always preserve these processes, indicating that other mechanisms involving neural stem cells support memory. It has been shown that intracerebroventricular delivery of neural stem cell-derived small extracellular vesicles in wild-type mice reduces cognitive decline and toxic oligomer binding to synapses. We hypothesize that adequate neural stem cell numbers support neural stem cell-derived small extracellular vesicles protection of synapses against Alzheimer's disease toxic oligomers. Here, we show that elements of immune response in the central nervous system, particularly microglia, may contribute to this protective effect. Specifically, fluorescent-labeled small extracellular vesicles injected into wildtype mice brains were taken up by microglia, with only neural stem cell-derived small extracellular vesicles causing increased microglial activation, indicated by CD68 immunostaining. RNA-sequencing data showed selective activation of immune pathways in microglia by neural stem cell-derived small extracellular vesicles, leading to greater activation and higher Tau uptake 24 hours post-neural stem cell-derived small extracellular vesicle administration. Single-nuclei RNAsequencing of hippocampal microglia gene revealed modulation related to lysosomal activity, supporting neural stem cell-derived small extracellular vesicleinduced neuroprotection via microglia. This study uncovers a novel mechanism through which neural stem cell-derived small extracellular vesicles enhance microglial activity and provide neuroprotection in the hippocampus. Our data demonstrates that neural stem cell-derived small extracellular vesicle uptake by microglia leads to increased microglial activation and improved uptake of Tau oligomers by microglia, suggesting that neural stem cell-derived small extracellular vesicles may prime microglia for a more effective immune response. These results support the hypothesis that neural stem cell-derived small extracellular vesicle-induced modulation of microglial function is crucial for preserving neuronal integrity and mitigating neurodegenerative processes. By elucidating the interactions between neural stem cell-derived small extracellular vesicles and microglia, our study opens new avenues for developing therapeutic strategies aimed at boosting microglial function and addressing neurodegenerative diseases such as Alzheimer's disease.},
}

@article {pmid41307192,
year = {2025},
author = {Banihashemi, MA and Krance, SH and Ji, PX and Koo, M and Ottoy, J and Swartz, RH and Kertes, PJ and Hudson, C and Goubran, M and Black, SE},
title = {Brain and retina in Alzheimer's disease: Pathological intersections and estimates from imaging.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70884},
doi = {10.1002/alz.70884},
pmid = {41307192},
issn = {1552-5279},
support = {/CAPMC/CIHR/Canada ; 177881//CIHR Graduate Scholarships Doctoral Award/ ; //Vision Science Research Program Award/ ; //Peterborough K.M. Hunter Graduate Scholarship/ ; //Queen Elizabeth II/Grace Lumsden and Margaret Nicholds Graduate Scholarship in Science & Technology (QEII-GSST)/ ; //Institute of Medical Science/University of Toronto Open Fellowship Award/ ; //SCACE Graduate Fellowship in Alzheimer Research/ ; //Ontario Graduate Scholarship/ ; 24AARF-1242638/ALZ/Alzheimer's Association/United States ; A2024012F//BrightFocus/ ; //Alzheimer Society of Canada/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; Tomography, Optical Coherence ; *Retina/pathology/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Biomarkers ; },
abstract = {Recent studies have highlighted retinal optical coherence tomography (OCT) imaging as a promising biomarker for the early detection of Alzheimer's disease (AD). This review connects AD brain pathology - particularly amyloid beta (Aβ), tau, and vascular changes - with corresponding retinal changes. Evidence suggests that abnormal Aβ and tau deposits in the retina may reflect brain pathology, though their formation mechanisms remain unclear. Retinal vascular changes may also mirror brain pathology, with recent data emerging on other co-pathologies. Retinal thickness changes, especially in acetylcholine-producing layers, can differentiate AD from controls, although not in early AD; however, emerging high-resolution OCT techniques may enhance early detection. We find that correlations between retinal thickness and brain structures are often weak, and retinal vascular imaging shows promise in estimating cerebrovascular disease markers from retinal vascular changes. Novel imaging modalities (e.g., hyperspectral imaging) for detecting retinal Aβ deposits may improve early AD screening when combined with other biomarkers. HIGHLIGHTS: Retinal Aβ/tau is equivocal; peripheral retinal p-tau shows diagnostic promise. OCT retinal/choroid thickness diagnostic/prognostic AUC is small to medium. Hyperspectral imaging and electroretinography may aid early diagnosis. OCTA may differentiate MCI from controls, but preclinical studies are needed. The added value of retinal biomarkers for risk stratification remains uncertain.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging
Tomography, Optical Coherence
*Retina/pathology/diagnostic imaging
*Brain/pathology/diagnostic imaging
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Biomarkers

@article {pmid41307180,
year = {2025},
author = {Guglielmo, S and Di Nardo, N and Scantamburlo, M and Mainardi, M and van den Oever, MC and Origlia, N},
title = {Chemogenetic manipulation of learning-tagged neurons is sufficient to rescue progressive memory deficits in a mouse model of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70953},
doi = {10.1002/alz.70953},
pmid = {41307180},
issn = {1552-5279},
support = {ECS_00000017//Ministry of University and Research PNRR/ ; DSB.AD005.225//CNR/ ; },
mesh = {Animals ; *Alzheimer Disease/genetics/complications ; Mice, Transgenic ; *Neurons/metabolism/physiology ; Disease Models, Animal ; Mice ; *Memory Disorders/etiology ; Entorhinal Cortex/metabolism ; Dentate Gyrus ; Proto-Oncogene Proteins c-fos/metabolism ; Amyloid beta-Protein Precursor/genetics ; Male ; *Learning/physiology ; Chemogenetics ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) primarily affects episodic memory, which relies on the medial temporal lobe, including the hippocampus and lateral entorhinal cortex (LEC). However, it remains unclear whether memory deficits in AD reflect disrupted encoding of new experiences or impaired retrieval of previously stored information.

METHODS: APPJ20 transgenic mice were used to investigate memory deficits. Neuronal populations activated during the learning phase of associative and non-associative tasks were tagged to express the excitatory chemogenetic receptor hM3Dq. Chemogenetic activation of these tagged neurons was performed during the recall phase of the tasks.

RESULTS: Chemogenetic reactivation of LEC or dentate gyrus (DG) learning-tagged neurons rescued memory performance in associative and non-associative tasks, respectively. Neuronal activation, assessed using c-Fos as a marker, revealed a specific deficit in the reactivation of neurons recruited during learning.

DISCUSSION: Chemogenetic reactivation of neuronal ensembles in the LEC and DG restored memory performance, suggesting that memory deficits in APPJ20 mice are associated with a failure in the endogenous reactivation of learning-relevant neurons.

HIGHLIGHTS: APPJ20 mice exhibited early entorhinal synaptic dysfunction and impaired episodic-like memory retrieval. At a later stage, hippocampal synaptic function became impaired, leading to altered non-associative memory performance. The analysis of neuronal activation using c-Fos revealed a specific impairment of the subpopulation recruited during memory encoding. Chemogenetic reactivation of LEC learning-tagged neurons rescued associative memory performance in 2-month-old APPJ20 mice, while promoting dendritic spine maturation and stabilization in LEC neurons. Chemogenetic reactivation of DG learning-tagged neurons in 6-month-old APPJ20 mice restored non-associative memory retrieval. This study supports the hypothesis that during AD progression, memory is encoded but not accessible through natural cues alone.},
}

Animals
*Alzheimer Disease/genetics/complications
Mice, Transgenic
*Neurons/metabolism/physiology
Disease Models, Animal
Mice
*Memory Disorders/etiology
Entorhinal Cortex/metabolism
Dentate Gyrus
Proto-Oncogene Proteins c-fos/metabolism
Amyloid beta-Protein Precursor/genetics
Male
*Learning/physiology
Chemogenetics

@article {pmid41307156,
year = {2025},
author = {Xu, Y and Qiao, M and Gunasekaran, TI and Gu, Y and Reyes-Dumeyer, D and Piriz, A and Sanchez, D and Soriano, B and Franco, Y and Coronado, ZD and Recio, P and Mejia, DR and Medrano, M and Lantigua, RA and Honig, L and Wilson, R and Manly, JJ and Brickman, AM and Engelman, CD and Johnson, S and Asthana, S and Vardarajan, B and Mayeux, R},
title = {Polygenic scores of Core 1 Alzheimer's disease biomarkers predict early cognitive and pathological change.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70937},
doi = {10.1002/alz.70937},
pmid = {41307156},
issn = {1552-5279},
support = {R01 AG067501/NH/NIH HHS/United States ; R01 AG072474/NH/NIH HHS/United States ; RF1 AG066107/NH/NIH HHS/United States ; UL1TR001873/TR/NCATS NIH HHS/United States ; R01 AG054047/AG/NIA NIH HHS/United States ; RF1 AG054047/AG/NIA NIH HHS/United States ; R01AG027161/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *Biomarkers/cerebrospinal fluid/blood ; Male ; Female ; *tau Proteins/cerebrospinal fluid/blood ; Aged ; Genome-Wide Association Study ; Positron-Emission Tomography ; *Multifactorial Inheritance/genetics ; Middle Aged ; Cognition ; Aged, 80 and over ; White People/genetics ; },
abstract = {INTRODUCTION: Core 1 biomarkers, such as amyloid positron emission tomography, capture the earliest biological changes leading to Alzheimer's disease (AD). While APOE is a major genetic factor, the contribution of other variants to Core 1 biomarkers remains unclear. The goal of this study was to determine whether genetic regulators of Core 1 biomarker levels predicted AD pathology better than genetic regulators of clinical AD.

METHODS: Among 955 non-Hispanic White individuals, polygenic scores (PGSs) were built using genome-wide association studies (GWASs) of amyloid PET, plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and clinical AD. Hispanic-specific PGSs were constructed in 515 individuals using plasma p-tau181 and clinical AD GWASs. Baseline and longitudinal associations with plasma biomarkers and cognition were assessed, and replication was conducted in separate cohorts.

RESULTS: The Core 1 biomarker PGSs predicted AD pathology and associated cognitive performance better than the AD PGSs in both populations.

DISCUSSION: The Core 1 PGSs show improved predictive value for AD-related plasma biomarkers and early cognitive changes.

HIGHLIGHTS: APOE ε4 explained more variance in plasma p-tau217 than in plasma p-tau181. PGSs based on Core 1 biomarkers outperformed AD PGSs in predicting plasma biomarkers and cognitive decline among asymptomatic individuals in non-Hispanic White and Hispanic individuals. However, the improvement in predictive power was modest and may vary by age. While the variance in p-tau181 and p-tau217 explained by individual Core 1 PGSs remains limited, the distinct genetic signals captured by the best-performing PGSs across different Core 1 biomarkers may provide an opportunity for developing an integrative Core 1 PGS that more effectively predicts plasma p-tau181 and p-tau217 levels than AD-based PGS.},
}

Humans
*Alzheimer Disease/genetics/pathology
*Biomarkers/cerebrospinal fluid/blood
Male
Female
*tau Proteins/cerebrospinal fluid/blood
Aged
Genome-Wide Association Study
Positron-Emission Tomography
*Multifactorial Inheritance/genetics
Middle Aged
Cognition
Aged, 80 and over
White People/genetics

@article {pmid41307069,
year = {2025},
author = {Zhang, Y and Qiu, J and Shang, Y and Zhao, X and Yang, S and Chen, Y and Dai, S and Ai, M and Huang, W and Zhang, J and Liu, X},
title = {Impact of DL-3-n-Butylphthalide on Progression in Alzheimer's Disease: A Retrospective Cohort Analysis.},
journal = {Neuropsychiatric disease and treatment},
volume = {21},
number = {},
pages = {2495-2511},
pmid = {41307069},
issn = {1176-6328},
abstract = {OBJECTIVE: To evaluate the efficacy of DL-3-n-butylphthalide (NBP), a synthetic compound that has shown neuroprotective effects, on cognitive function, psychiatric-behavioral symptoms, and daily activities in patients with Alzheimer's disease (AD).

METHODS: This retrospective cohort study included patients with AD treated with or without NBP. Disease deterioration and decline were defined by changes in Clinical Dementia Rating-Sum of Boxes (CDR-SB) over six months. Multivariate logistic regression, inverse probability of treatment weighting (IPTW) and overlap-weighted propensity score matching (PSM) were used to adjust for confounding.

RESULTS: Totally 100 were included in this study, with 39 classified as the NBP group and 61 as the non-NBP group. NBP was associated with lower odds of deterioration (adjusted odds ratio [OR] = 0.19, 95% confidence interval [CI]: 0.04-0.88, p = 0.034) and decline (adjusted OR = 0.10, 95% CI: 0.03-0.49, p = 0.001). In IPTW and PSM analyses, deterioration occurred in 4.31% vs 22.10% and 4.06% vs 24.27%, and decline in 4.31% vs 39.38% and 4.06% vs 44.28% for the NBP and non-NBP groups, respectively.

CONCLUSION: NBP was associated with reduced risks of clinical worsening and helped preserve cognitive and behavioral functions in patients with AD. These results highlight the potential of NBP as a promising therapeutic option in AD management. Future randomized controlled trials are necessary to validate these findings and assess the long-term efficacy of NBP in clinical settings.

SIGNIFICANCE: This real-world study suggests that NBP may slow disease progression and preserve cognitive and behavioral function in AD.},
}

@article {pmid41306975,
year = {2025},
author = {Lee, HJ and Kang, S and Lee, YJ and Oh, S and Joo, B and Hwang, JW and Kim, J and Kim, TE and Jung, TM and Kim, YJ and Jang, JY and Song, JH and Koo, JW and Hoe, HS},
title = {Genetic knockdown of DYRK1A attenuates cognitive impairment, Aβ pathology, tauopathy and neuroinflammatory responses in mouse models of AD.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1661791},
pmid = {41306975},
issn = {1664-3224},
mesh = {Animals ; Dyrk Kinases ; *Protein-Tyrosine Kinases/genetics/metabolism ; Mice ; Disease Models, Animal ; *Alzheimer Disease/genetics/pathology/metabolism ; *Protein Serine-Threonine Kinases/genetics/metabolism ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Cognitive Dysfunction/genetics/metabolism/pathology ; *Tauopathies/genetics/pathology/metabolism ; Hippocampus/metabolism/pathology ; *Neuroinflammatory Diseases/genetics/pathology/metabolism ; Male ; Gene Knockdown Techniques ; Humans ; Mice, Inbred C57BL ; },
abstract = {INTRODUCTION: Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is associated with the pathoprogression of neurodevelopmental and neurodegenerative disorders. However, the effects of direct genetic manipulation of DYRK1A in the brain on cognitive function, neuroinflammation and Alzheimer's disease (AD) pathology and underlying molecular mechanisms have not been fully investigated.

METHODS: To determine whether overexpressing or knocking down DYRK1A expression directly in the brain affects cognitive function, neuroinflammation and AD pathology, adeno-associated viruses (AAVs) were injected into the hippocampus of wild-type (WT), 5xFAD, and PS19 mice. Then, cognitive function was assessed via Y-maze and novel object recognition (NOR) tests, and neuroinflammatory responses and AD pathologies were analyzed by real-time PCR, Western blotting, immunofluorescence staining, AD-associated protein activity assays and ELISA.

RESULTS AND DISCUSSION: In WT mice, hippocampal DYRK1A overexpression significantly reduced short-term spatial/recognition memory and SynGAP expression while increasing p-P38 levels. Conversely, in amyloid-beta (Aβ)-overexpressing 5xFAD mice, hippocampal DYRK1A knockdown improved short-term spatial/recognition memory and significantly increased CaMKIIα and CREB phosphorylation. Moreover, hippocampal DYRK1A knockdown in 5xFAD mice significantly suppressed mRNA levels of proinflammatory cytokines and markers of AD-associated reactive astrocytes (RAs), disease-associated microglia (DAMs), and RA-DAM interactions. However, hippocampal DYRK1A overexpression in 5xFAD mice increased mRNA levels of the proinflammatory cytokine IL-1β, RA markers and the microglial marker Iba-1. Interestingly, hippocampal DYRK1A knockdown in 5xFAD mice significantly increased levels of the anti-oxidative/inflammatory molecule HO-1 without altering p-STAT3/p-NF-κB levels. By contrast, hippocampal DYRK1A overexpression in 5xFAD mice enhanced STAT3/NF-κB phosphorylation but did not affect ROS levels. Importantly, hippocampal DYRK1A knockdown in 5xFAD mice significantly reduced Aβ plaque number, soluble Aβ40 levels, and soluble/insoluble Aβ42 levels by suppressing β-secretase BACE1 activity but not tau hyperphosphorylation. Finally, hippocampal DYRK1A knockdown in PS19 mice [a model of AD that overexpresses human mutant tau (P301S)] selectively decreased insoluble tau hyperphosphorylation at Ser396 and Ser404 and alleviated proinflammatory responses/glial-associated neuroinflammatory dynamics. Taken together, our data indicate that DYRK1A modulates cognitive function, neuroinflammation, and AD pathology (Aβ and tauopathy) in mouse models of AD and/or WT mice and support DYRK1A as a potential therapeutic target for AD.},
}

Animals
Dyrk Kinases
*Protein-Tyrosine Kinases/genetics/metabolism
Mice
Disease Models, Animal
*Alzheimer Disease/genetics/pathology/metabolism
*Protein Serine-Threonine Kinases/genetics/metabolism
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Cognitive Dysfunction/genetics/metabolism/pathology
*Tauopathies/genetics/pathology/metabolism
Hippocampus/metabolism/pathology
*Neuroinflammatory Diseases/genetics/pathology/metabolism
Male
Gene Knockdown Techniques
Humans
Mice, Inbred C57BL

@article {pmid41306895,
year = {2025},
author = {Duncan, GB and Dickson, SP and Kaplan, JM and Johnson, SB and Duke, TM and Dayley, CW and Hendrix, SB and Altstiel, LD and Mallinckrodt, CH},
title = {Leveraging recent advances in plasma biomarkers to optimize early proof of concept trials in Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70183},
pmid = {41306895},
issn = {2352-8737},
abstract = {INTRODUCTION: The importance of biomarkers as a primary outcome or as supportive evidence of clinical effect is rising as the field shifts toward disease-modifying treatments and earlier intervention, because they have lower variability and can indicate disease progression earlier than clinical outcomes. This study assessed the performance of plasma pTau 181 and 217 as a predictive biomarker and potential primary endpoint in early-phase Alzheimer's disease (AD) trials.

METHODS: Summary data from recent monoclonal antibody (mAb) trials including plasma pTau 181 and 217 were analyzed to evaluate associations between plasma pTau 181/217 and clinical outcomes. The suitability of plasma pTau 181/217 as a surrogate endpoint for internal decision making was assessed using Prentice criteria. Simulations were conducted to explore the statistical power of using plasma pTau 181/217 as a primary outcome in dose-escalation, proof-of-concept (POC) trial designs. Additional criteria for biomarker validation were applied to simulated data.

RESULTS: A strong group-level correlation (r = 0.781) was observed between treatment effects on plasma pTau 181/217 and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB). Mean change in plasma pTau 181/217 significantly predicted mean change in CDR-SB (p = 0.013). The treatment effect on pTau 181/217 was ∼2.6 times greater than on CDR-SB. Prentice Criteria 1, 2, and 4 were met or reasonably met; Criterion 3 is not applicable in the POC setting.

CONCLUSION: Plasma pTau 181/217 at 6 months shows future promise to reasonably likely predict clinical benefit for drugs that reduce pTau 181/217 levels, supporting its use as a primary endpoint in early-phase trials. With effect sizes similar to those seen with donanemab, adequately powered trials may require as few as 100 participants. Such trials should include prespecified analyses to evaluate individual-level Prentice criteria, and pTau 181/217 results can be used to predict potential Phase 3 clinical outcomes.

HIGHLIGHTS: The group-level correlation between a biomarker treatment effect and clinical endpoint treatment effect is a measurement of the biomarker's ability to predict clinical outcome.The correlation of group level plasma pT217 or pT181 effect size at 6 months with clinical outcome Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) effect size at 12 months was approximately 0.781 with p values of 0.013.Cohen's d effect size of plasma pTau as an outcome was 2.6 times greater than the Cohen's d of CDR-SB, leading to higher power or lower sample sizes.As a primary endpoint, plasma pTau meets or reasonably meets Prentice Criteria 1, 2, and 4, while Criterion 3 was deemed not applicable in the proof-of-concept study setting.},
}

@article {pmid41306777,
year = {2025},
author = {Xu, M and Zhu, Y and Chen, J and Zhong, F and Wang, R and Li, J and Qiao, M and Fan, Y and Ren, P and Chen, M and Qin, J and Wu, W},
title = {Differential effects of Huang-Lian-Jie-Du Decoction on Alzheimer's disease and normal rats.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1710919},
pmid = {41306777},
issn = {1663-9812},
abstract = {INTRODUCTION: Huang-Lian-Jie-Du Decoction (HLJDD), a botanical drug used in traditional medicine, has been used in the management of Alzheimer's disease (AD). However, the mechanisms underlying its preventive effects remain inadequately understood, particularly due to the absence of metabolomic studies examining alterations in serum and cerebrospinal fluid (CSF) metabolites. Moreover, the potential toxicities and side effects of HLJDD necessitate further pharmacological investigation. This study aims to explore the differential effects of HLJDD on AD model rats and healthy controls through a metabolomics approach and uncover the underlying mechanisms based on changes in serum and CSF metabolites. The findings are expected to provide a scientific foundation for enhancing the clinical safety and rational use of HLJDD.

METHODS: The composition of HLJDD was characterized by UPLC-Q-Exactive Orbitrap HRMS. Aβ1-42-induced SD rats served as the AD animal model. Rats in the sham + HLJDD and Aβ1-42 + HLJDD groups (0.604 g/kg freeze-dried powder) were treated with HLJDD via gavage for 28 days. Nissl staining was performed to assess hippocampal neuronal changes, while H&E staining was used to evaluate histopathological alterations in the brain, liver, kidneys, stomach, large intestine, and small intestine. Aβ expression was determined using IHC and ELISA, and inflammatory levels in both peripheral and central systems were quantified by ELISA. MMP-2 and MMP-9 expression were analyzed through IHC. LC-MS was employed to investigate metabolic variations in serum and CSF.

RESULTS: HLJDD reduced Aβ deposition in Alzheimer's disease rats, enhanced neuronal survival, reduced inflammation, preserved blood-brain barrier (BBB) integrity, and alleviated damage to the brain, kidneys, and stomach. These therapeutic effects were associated with the arginine biosynthesis pathway and ferroptosis. In contrast, HLJDD induced peripheral and central inflammation, impaired neuronal function, compromised BBB integrity, and caused damage to the liver, kidneys, and large intestine in normal rats. These adverse effects were linked to disruptions in aminobenzoate degradation and nucleotide metabolism.

CONCLUSION: HLJDD may alleviate Aβ-induced damage repair in Alzheimer's disease rats, but it also induces varying degrees of toxicity in normal rats.},
}

@article {pmid41306676,
year = {2025},
author = {Khan, T and Anwar, Z and Altaf, R and Awan, A and Noreen, A and Usmani, M and Ejaz, MA and Khan, A and Ahmed, S and Sheraz, MA and Ali, T},
title = {Riboflavin-sensitized photoinduced degradation of donepezil hydrochloride: kinetic and computational insights for pharmaceutical formulation.},
journal = {RSC advances},
volume = {15},
number = {53},
pages = {45799-45821},
pmid = {41306676},
issn = {2046-2069},
abstract = {Donepezil (DPZ) photosensitized degradation by riboflavin (RF) at pH 2.0-12.0 has been carried out in aerobic and anaerobic conditions under UV and visible irradiation to give an idea to pharmaceutical formulators to develop a stable co-formulation to administer to elderly patients with neurodegenerative diseases (Alzheimer's disease, Parkinson's disease). The photolysis rate constants (k obs) in aerobic and anaerobic conditions in the presence of RF (0.1-0.5 × 10[-4] M) range from 0.25-11.5 and 0.025-1.120 × 10[-2] min[-1], respectively. RF catalyzes the photodegradation of DPZ, and the second-order (k 2) constants in aerobic and anaerobic conditions range from 0.32 to 8.22 and 0.032 to 0.805 × 10[-2] M[-1] min[-1], respectively, indicating that with an increase in the concentrations of RF, the rate of photolysis of DPZ also increases. The k-pH profile shows a bell-shaped curve from pH 2.0 to 4.0 and from pH 5.0 to 12.0, forming a sigmoid curve. The two-component spectrometric and HPLC green methods have been developed and validated for estimating DPZ and RF in pure and degraded solutions. Additionally, computational studies have been conducted to assess the formation of the ground-state complex, binding affinity, and molecular interactions between DPZ and RF.},
}

@article {pmid41306639,
year = {2025},
author = {Bocti, C and Bergman, H},
title = {Anti-Amyloid Therapies for Alzheimer's Disease: Not the Way Forward.},
journal = {Canadian geriatrics journal : CGJ},
volume = {28},
number = {4},
pages = {400-402},
pmid = {41306639},
issn = {1925-8348},
}

@article {pmid41306598,
year = {2025},
author = {Overson, DK and Truong, TK and Petrella, JR and Madden, DJ and Ma, Y and Johnson, KG and Liu, AJ and O'Brien, RJ and Whitson, HE and Song, AW},
title = {Predicting risk of impending cognitive decline in asymptomatic individuals with early Alzheimer's disease: Insights from cortical diffusion MRI.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {3},
number = {},
pages = {},
pmid = {41306598},
issn = {2837-6056},
abstract = {Neurodegeneration associated with Alzheimer's disease (AD) can start at the microstructural level years before cognitive symptoms; yet, it has been difficult to definitively detect these early changes to plan effective treatments. Using a cortical column-based analysis of high-resolution diffusion magnetic resonance imaging data, we aim to identify early microstructural neurodegeneration in the gray matter across different cortical depths and regions. We compared four groups of participants across a spectrum of cognitive decline (n = 60): cognitively normal amyloid-negative (normal controls), cognitively normal amyloid-positive (stage-1 AD), mild cognitive impairment (MCI), and AD dementia. Our results showed progressive increases in radial diffusivity across these groups in cortical regions associated with AD, and our analysis in individual asymptomatic stage-1 AD participants was able to differentiate such diffusivity increases to predict risk of impending cognitive decline in 2 participants who had cognitive decline and MCI diagnosis at their follow-up clinical examination and 11 participants who did not.},
}

@article {pmid41306540,
year = {2025},
author = {Cordi, CV and Hurley, JM},
title = {The Link Between Circadian Disruption and Alzheimer's Disease and Related Dementias: Insights from Peripheral Inflammation.},
journal = {Current opinion in physiology},
volume = {46},
number = {},
pages = {},
pmid = {41306540},
issn = {2468-8673},
abstract = {Circadian rhythms are essential for maintaining physiological homeostasis, influencing biological processes from the sleep-wake cycle to metabolism and immune responses. Disruption of these rhythms is increasingly linked to the pathogenesis of Alzheimer's Disease and Related Dementias (ADRDs), conditions characterized by cognitive decline and neuropsychiatric symptoms through various pathways including increases in inflammation. While many studies link the effects of circadian disruption on neuroinflammation to ADRDs, this review explores the potential link between the circadian disruption of peripheral inflammation and ADRDs. We discuss the evidence of how circadian misalignment can exacerbate neuroinflammation through the activation of the peripheral immune system. We further examine the role of peripheral factors such as insulin dysregulation, melatonin levels, and gut microbiome imbalances in amplifying these peripheral inflammatory responses. These data underscore the significance of circadian regulation in maintaining immune homeostasis, highlighting potential therapeutic avenues for mitigating ADRDs through the restoration of circadian integrity.},
}

@article {pmid41306424,
year = {2025},
author = {Anil, N and McLouth, CJ and Hazelwood, HS and Dahlke, E and Frank, JA and Millson, N and Al-Kawaz, M and Harp, JP and Cranford, W and Pahwa, S and Dornbos, D and Fraser, JF and Pennypacker, KR},
title = {Expression of dementia biomarkers in Appalachian and non-Appalachian ELVO patients during thrombectomy.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1672803},
pmid = {41306424},
issn = {1662-4548},
abstract = {BACKGROUND/CONTEXT: Vascular Cognitive Impairment and Dementia (VCID) affects 25-30% of stroke patients and includes cognitive impairments caused by vascular injury, such as post-stroke dementia. Rehabilitation has the potential to improve the quality of life for patients at risk of developing dementia. However, there is currently no reliable method to identify those at risk of dementia after a stroke. Several biomarkers, including ADRD (Alzheimer's disease and related dementias) biomarkers (Ab, tau, NfL, and GFAP) and angiogenic factors (VEGF, Flt-1, Tie-2, PIGF, and FGF) have been associated with the development of dementia.Populations in Appalachia experience a higher incidence of stroke and related mortality compared to other groups. Given the elevated stroke rates in Appalachian communities, this study aims to investigate potential proteomic differences between patients from Appalachian and non-Appalachian counties. The primary goal of the study is to characterize the expression of post-stroke cognitive dementia biomarkers and to explore differences in the proteomic profiles of Appalachian and non-Appalachian populations.

METHODS/APPROACH: Sample Collection: The Blood and Clot Thrombectomy Registry Collaborative (BACTRAC) protocol, established by Fraser and colleagues, introduces a novel method for analyzing stroke by collecting intracranial blood samples from patients undergoing mechanical thrombectomy. During the procedure the thrombus and blood samples from areas distal and proximal to the thrombus are collected and undergo proteomic analysis (Fraser et al.). Additional demographic and clinical information are collected from electronic health records. The control data was obtained from arterial blood collected during diagnostic angiograms from patients with cerebrovascular disease.

DATA ANALYSIS: Propensity score models were used to perform a one-to-one match between stroke and control patients on age, sex, BMI, hypertension, and hyperlipidemia resulting in groups that were balanced on these measured prognostic characteristics. A Wilcoxon rank sum test was then used to assess differences in the 12 ADRD biomarkers.

RESULTS: Compared to the controls, stroke patients had significantly higher levels of GFAP. The control patients had significantly higher levels of AB40, AB42, and VEGFA. In the Appalachian patient population, the control patients also had significantly higher levels of AB40, AB42, and VEGFA. Additionally, the Appalachian stroke patients had higher GFAP. In the non-Appalachian population only GFAP was significantly different between stroke and control groups, with it being elevated in the stroke group.

CONCLUSION: There was a notable difference in the levels of certain ADRD biomarkers between stroke patients and control patients. Specifically, in Appalachian populations, stroke patients showed significant differences in multiple ADRD biomarkers (AB40, AB42, and GFAP) compared to controls, a pattern not seen in non-Appalachian stroke patients, where only GFAP levels increased. This difference in ADRD biomarkers observed in Appalachian stroke patients could be attributed to a combination of socioeconomic and environmental factors unique to the Appalachian region.},
}

@article {pmid41306402,
year = {2025},
author = {Riberas-Sánchez, A and García-Brito, S and Vila-Solés, L and Aldavert-Vera, L and Segura-Torres, P and Huguet, G and Carreras-Badosa, G and Kádár, E},
title = {Intracranial self-stimulation mitigates spatial task deficits, modifies miR-146a and miR-495 serum levels and restores hippocampal NRF2 levels in a rat model of sporadic Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1671196},
pmid = {41306402},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease associated with aging. While deep brain stimulation (DBS) shows therapeutic promise, the long-term persistence of its effects remains understudied. Expression patterns of circulating miRNAs, proposed diagnostic biomarkers, and their modulation by DBS are still poorly characterized in longitudinal studies. This study investigates the effect of a 13-week prolonged ICSS treatment on spatial memory and serum miRNA expression in a male rat model of sporadic AD (SAD) by intracerebroventricular injection of streptozotocin (STZ).

METHODS: Morris water maze (MWM) tasks were conducted at 1 and 5 months post-STZ. Serum miRNA levels were quantified by qRT-PCR at 29 (Ser0), 73 (Ser1) and 136 (Ser2) days after STZ administration. Corpus callosum thickness and NRF2 protein levels in the hippocampal CA1 region were assessed using Nissl staining and immunohistochemistry, respectively. Target validation of miR-495 was performed via transfection assays in the human neuroblastoma SH-SY5Y cell line.

RESULTS: MFB-ICSS treatment significantly reduced escape latency in the MWM task in the STZ + ICSS group compared to untreated STZ rats at 5 months post-STZ. At Ser0, levels of miR-16, miR-30c, miR-181, miR-191 and miR-196a were significantly increased in STZ group. In STZ rats, miR-146a and miR-495 levels increased from Ser1 to Ser2, an effect not observed in the Control or STZ + ICSS groups. In SH-SY5Y cells, miR-495 overexpression significantly downregulated both NRF2 mRNA and protein levels. Moreover, STZ exposure increased miR-495 and reduced NRF2 protein levels. MFB-ICSS also reversed the STZ-induced reductions in both CA1 NRF2 levels and corpus callosum thickness.

CONCLUSION: Prolonged MFB-ICSS treatment mitigates cognitive deficits, modulates circulating levels of miRNA-495 and miR-146a, restores hippocampal NRF2 levels, and preserves corpus callosum integrity in the SAD rat model by STZ injection. These findings highlight the therapeutic potential of MFB-ICSS as a non-pharmacological intervention in AD. Furthermore, this study confirms NRF2 as a target of miR-495 in the context of AD.},
}

@article {pmid41306381,
year = {2025},
author = {Ng, TK},
title = {Clarifying blood-based brain-derived neurotrophic factor measurement in Alzheimer's disease research: A call for pre-analytic standardization.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251399060},
pmid = {41306381},
issn = {2542-4823},
abstract = {The study by Kueck et al. rigorously addresses the complex pre-analytical and biological confounds underlying blood-based brain-derived neurotrophic factor (BDNF) measurement in Alzheimer's disease (AD) research. By directly comparing platelet-rich plasma and platelet-poor plasma, it distinguishes free-circulating from platelet-stored BDNF and their associations with core AD biomarkers. Findings support BDNF as a potential compensatory marker in early cognitive impairment and emphasize the critical need for biomarker-specific pre-analytic standardization protocols. This commentary contextualizes the work within existing inconsistencies and outlines key recommendations for standardizing blood-based BDNF measurements to ensure reproducibility, potential clinical utility, and translational relevance.},
}

@article {pmid41306308,
year = {2025},
author = {Sun, H and Song, Y},
title = {Invisible Invaders: How Nanoplastics Hijack the Brain and Accelerate Alzheimer's Pathology.},
journal = {Environment & health (Washington, D.C.)},
volume = {3},
number = {11},
pages = {1264-1265},
pmid = {41306308},
issn = {2833-8278},
}

@article {pmid41306300,
year = {2025},
author = {Wang, Y and Liang, X and Andrikopoulos, N and Zheng, S and Li, Y and Ke, PC},
title = {Cerebral to Systemic Representations of Alzheimer's Pathogenesis Stimulated by Polystyrene Nanoplastics.},
journal = {Environment & health (Washington, D.C.)},
volume = {3},
number = {11},
pages = {1380-1392},
pmid = {41306300},
issn = {2833-8278},
abstract = {Plastics discharged into the ecosphere can transform into micro- and nanoparticles to instigate interactions with biosystems, posing a threat to environmental sustainability and human health. While nanoplastics have recently been identified in abundance in the human brain, especially in the decedent brain tissues of dementia subjects, how these exogenous miniatures mediate neurological as well as systemic pathologies remains unclear. Here, we first investigated how environmental-level nanoplastic exposure influences the progression of Alzheimer's disease, from cerebral to systemic representations. Specifically, polystyrene nanoplastics aggravated Alzheimer's-like symptoms in both wild-type and APP/PS1 mice and stimulated microglial activation and hippocampal neuronal death, accentuated by peripheral abnormalities of lipid accumulation, hepatic steatosis, inflammation, adipocyte enlargement, and gut microbiota imbalance. These findings implicate that nanoplastic-induced neurological damage is not confined within the brain but expands systemically through the gut-liver-brain axis, thereby contributing to the multiscale and multidirectional progression of Alzheimer's pathophysiology.},
}

@article {pmid41306192,
year = {2026},
author = {Zhang, Y and Zhang, H and Shen, Z},
title = {Control analysis of deep brain stimulation and optogenetics for Alzheimer's disease under the computational cortex model.},
journal = {Cognitive neurodynamics},
volume = {20},
number = {1},
pages = {10},
pmid = {41306192},
issn = {1871-4080},
abstract = {Abnormal τ and β-amyloid (Aβ) deposition in the brains of patients with Alzheimer's disease (AD) is significantly associated with cognitive decline. This abnormal deposition has been reported to be linked to increased excitatory and inhibitory time constants in neural circuits. In this paper, we focus on three typical electroencephalography (EEG) slowdowns clinically reported in association with AD, including decreased dominant frequency, decreased α rhythmic activity, and increased δ + θ rhythmic activity. Firstly, we demonstrate that changes in excitatory time constant, inhibitory time constants, and synaptic connection strength can induce the phenomenon of EEG slowdowns in early AD. Then, we are interested in the regulation of AD by traditional deep brain stimulation (DBS) and emerging optogenetic stimulation. High-frequency, high-pulse width, and high-amplitude DBS are more effective in reversing brain rhythm in AD, supporting the experiment that cortical high-frequency DBS may be an effective therapeutic way for dementia-related diseases. In particular, as a modification of traditional DBS, we find that oscillatory bursty stimulation can compensate for the shortcomings of DBS at low amplitude. However, it is physiologically difficult to target inhibitory interneurons with conventional electrical stimulation. Optogenetics is able to precisely stimulate pyramidal neurons and inhibitory interneurons observed in animal experiments. Our numerical results indicate that medium and low-frequency stimulation can better eliminate AD pathology. It should be noted that stimulation of inhibitory interneurons requires greater light intensity than stimulation of pyramidal neurons. Finally, we propose two optimization intermittent optogenetic stimulation protocols. These modeling results can reproduce some experimental phenomena and are expected to reveal the underlying pathological mechanisms and control strategies associated with cognitive dysfunction such as AD.},
}

@article {pmid41306115,
year = {2025},
author = {Li, G and Cobb, B and Nelson, TM and Devanarayan, V and Borentain, S and Mielke, MM and Galvin, JE and Kivipelto, M and Tkatch, R and De Santi, S and Frech, F and Vandercappellen, J and Nakamura, Y and Crislip, R and Meyerhoff, J and Mattke, S and Hampel, H},
title = {Risk prediction of mild cognitive impairment using electronic health record data.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70209},
pmid = {41306115},
issn = {2352-8729},
abstract = {INTRODUCTION: Mild cognitive impairment (MCI) is underdiagnosed by primary care providers (PCPs), with detection rates as low as 6%-15%. Predictive models support the identification of individuals at risk, enabling timely intervention.

METHODS: This retrospective study was conducted on 271,054 cognitively unimpaired and 14,501 confirmed MCI cohorts from electronic health records. A machine learning model was developed with a data-driven variable selection approach based on demographics and comorbidities.

RESULTS: From 101 variables, 26 were chosen for the final model, achieving an overall area under the curve (AUC) of 86%. Age-stratified AUCs were 79.1% (40-49), 77.0% (50-64), 76.9% (65-79), and 74.4% (≥80), showing the highest predictive performance in younger age groups.

DISCUSSION: Demographic factors and comorbidities can serve as effective predictors for the risk of MCI. The model demonstrates strong predictive performance and assists as a triage tool for PCPs, facilitating the identification of individuals with MCI for early treatment.

HIGHLIGHTS: Predictive algorithms using electronic health records (EHRs) are useful for identifying individuals at risk for mild cognitive impairment (MCI) to triage for further clinical evaluation.A machine learning model was developed using EHR data to predict those at risk for MCI.The model identified 26 variables that were able to distinguish the MCI from non-MCI cohorts.The model accurately detected MCI across the cohort (area under the curve [AUC] = 86%) and trended best for younger age groups (AUC was 77%, 77%, and 74% in 50-64, 65-79, and ≥80 age groups, respectively).Implementation of a triage tool could be used to detect MCI across aging patient populations sooner, leading to a timelier diagnosis, intervention, and treatment management.},
}

@article {pmid41305902,
year = {2025},
author = {Zheng, Z and Tang, Z and Li, C and Xiao, H and Li, Y and He, A and Mao, Y and Zheng, J and Ke, M and Gao, R and Li, D and Liu, C and Dong, Z and Tian, R},
title = {In-Situ Spatial Visual Proteomics Enabled by Single-Cell-Type Proximity Biotinylation and Signaling Amplification.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e19440},
doi = {10.1002/anie.202519440},
pmid = {41305902},
issn = {1521-3773},
abstract = {Mapping the spatial proteome signature within heterogeneous tissue microenvironment of clinical specimens offers unique insights into both physiological and pathological molecular phenotypes. However, to simultaneously visualize and discover these spatial proteome features is challenging. Herein, we introduce spatial visual proteomics (SVPro) which integrates single-cell proximity biotinylation coupled with fluorescence signal amplification via the trifunctional probe. This probe uniquely combines naphthylamine-mediated radical targeting, clickable fluorescence imaging, and biotinylation-facilitated proteome capture, enabling all three within a single tissue section. Strategic PEGylation and multivalent fluorescent conjugation of these probes improves labeling and visualization efficiency and specificity. SVPro allows cell-type proteomic profiling of neuronal subpopulations in distinct mouse brain regions and amyloid-β plaques in mouse brain of Alzheimer's disease model. Notably, we identified and validated distinct marker proteins associated with amyloid‑β plaques deposited in different brain regions. SVPro therefore emerges as a robust and high-resolution spatial proteomics approach for simultaneously visualizing the spatial architecture and proteome landscapes of intact tissue microenvironment.},
}

@article {pmid41305866,
year = {2025},
author = {Naderi, S and Williamson, J and Sun, H and Joshi, S and Spera, RJ and Zaib, S and Sharma, S and Sun, C and Brodovskiy, A and Zawar, I and Kapur, J},
title = {Hydroxycarboxylic Acid Receptor 2 Mediates β-hydroxybutyrate's Antiseizure Effect in Mice.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78098},
pmid = {41305866},
issn = {1531-8249},
support = {R01NS120945//United States National Institute of Health (NINDS)/ ; R37N119012//United States National Institute of Health (NINDS)/ ; },
abstract = {OBJECTIVE: The ketogenic diet, a high-fat, low-carbohydrate regimen, is often used to treat drug-resistant seizures and is being studied for Alzheimer's disease and other neuropsychiatric disorders. However, its mechanism of action remains unclear. β-hydroxybutyrate, a primary circulating ketone body produced by the ketogenic diet, may mediate its effects on seizures by binding to a recently identified Gi-coupled receptor: hydrocarboxylic acid receptor 2 (HCAR2).

METHODS: RNAscope in situ hybridization assay and real-time quantitative polymerase chain reaction were used to assess HCAR2 expression in the mouse brain. We generated HCAR2[-]/[-] using the CRISPR-Cas technique on an S129 mouse background. Whole-cell current-clamp was performed to measure the passive and active membrane properties of hippocampal dentate granule cells. The voltage-clamp was performed to record synaptic currents. Two complementary in vivo mouse models-continuous hippocampal stimulation to induce status epilepticus (SE) and kindling-were used to induce seizures.

RESULTS: HCAR2 was localized in dentate granule cells and microglia. In mice with HCAR2, β-hydroxybutyrate reduced neuronal excitability by hyperpolarizing the resting membrane potential, raising the action potential threshold, and reducing the firing frequency of dentate granule cells. β-hydroxybutyrate suppressed excitatory synaptic transmission. These effects were nullified in HCAR2[-]/[-] mice. HCAR2[-]/[-] mice showed no cognitive impairment. Moreover, β-hydroxybutyrate did not affect seizures in HCAR2[-]/[-] mice. However, it diminished both the duration and severity of seizures in HCAR2[+]/[+] mice.

INTERPRETATION: These findings demonstrate that HCAR2 mediates β-hydroxybutyrate's antiseizure effects by regulating neuronal excitability and synaptic transmission. These studies propose a new mechanism for the antiseizure action of the ketogenic diet. ANN NEUROL 2025.},
}

@article {pmid41305738,
year = {2025},
author = {Chen, B and Chen, Y and Zhang, J and Yang, W and Xu, Y and Chen, X and Chen, N and Xia, J and Xia, J and Ding, H and Yang, T},
title = {Alzheimer's and Parkinson's diseases in relation to human papillomavirus infection: A two-sample Mendelian randomization study.},
journal = {Medicine},
volume = {104},
number = {47},
pages = {e46043},
doi = {10.1097/MD.0000000000046043},
pmid = {41305738},
issn = {1536-5964},
mesh = {Humans ; Mendelian Randomization Analysis ; *Alzheimer Disease/virology/genetics/epidemiology ; *Parkinson Disease/virology/genetics/epidemiology ; *Papillomavirus Infections/complications/epidemiology/genetics ; Genome-Wide Association Study ; Risk Factors ; Papillomavirus E7 Proteins/blood ; Female ; Male ; Human papillomavirus 16 ; Human papillomavirus 18 ; },
abstract = {An increasing number of studies are exploring links between human papillomavirus (HPV) infection and neurodegenerative diseases. Yet, existing evidence from retrospective studies is prone to bias and cannot confirm causation. To address this, our 2-sample Mendelian randomization (MR) study utilizing single nucleoside polymers aims to establish a potential causal connection between HPV and the onset of Alzheimer disease (AD) and Parkinson disease (PD). We utilized a 2-sample MR approach to evaluate the causal relationships between HPV16 and HPV18 E7 proteins, HPV seropositivity, and the risks of AD and PD. Selected single nucleoside polymers from genome-wide association studies served as instrumental variables in HPV exposure data for MR analysis. Subsequent rigorous sensitivity assessments were also performed to ensure robustness. In this research, we explored the potential causal connections between HPV infection and the development of AD or PD through a MR analysis. Our findings suggest that the HPV18 E7 protein might act as a protective factor against PD, whereas HPV seropositivity was recognized as a risk factor for the same condition. Interestingly, neither the HPV16 E7 protein nor HPV seropositivity appeared to have any significant impact on the risk of AD. These findings shed light on HPV's intricate involvement in neurodegenerative diseases, offering fresh views on viral impacts on disorders like PD and AD. Recognizing study limitations, further research is crucial to confirm and clarify HPV's exact effects on these conditions.},
}

Humans
Mendelian Randomization Analysis
*Alzheimer Disease/virology/genetics/epidemiology
*Parkinson Disease/virology/genetics/epidemiology
*Papillomavirus Infections/complications/epidemiology/genetics
Genome-Wide Association Study
Risk Factors
Papillomavirus E7 Proteins/blood
Female
Male
Human papillomavirus 16
Human papillomavirus 18

@article {pmid41305668,
year = {2025},
author = {Paules, EM and Petry, HG and Sprinkles, JK and Trujillo-Gonzalez, I},
title = {Future Directions in Choline: From Neurodevelopment to Cardiometabolic Health.},
journal = {Nutrients},
volume = {17},
number = {22},
pages = {},
doi = {10.3390/nu17223618},
pmid = {41305668},
issn = {2072-6643},
support = {N/A//Nutrition Research Institute, start up to I. T-G/ ; R01 DK115380/DK/NIDDK NIH HHS/United States ; },
mesh = {Humans ; *Choline/metabolism/administration & dosage ; Pregnancy ; *Cardiovascular Diseases/prevention & control/metabolism ; Female ; Brain/metabolism/drug effects ; Cognition/drug effects ; Obesity/metabolism ; Methylamines/metabolism ; Animals ; Dietary Supplements ; },
abstract = {Although choline was established as an essential nutrient over three decades ago, critical questions remain about how choline regulates brain, liver, and cardiometabolic health across the lifespan. This Perspective summarizes emerging insights presented at the Future Directions in Choline Symposium: A Tribute to Steven H. Zeisel, which outlined three converging areas of research: (i) choline-dependent mechanisms in neurodevelopment and cognition, (ii) the link between choline metabolism and obesity, and (iii) the role of trimethylamine N-oxide (TMAO) in cardiovascular disease. Evidence from clinical and preclinical studies confirms that maternal choline intake is critical for neurogenesis, cognition, and visual system development, and that higher choline availability buffers the fetal brain against environmental and psychosocial stressors. Choline supplementation improves cognitive outcomes in fetal alcohol spectrum disorder and mitigates neurodegenerative pathology in Alzheimer's models. In cardiometabolic health, recent data challenge the interpretation of TMAO as a causal toxin, positioning it instead as a marker of renal function. Moving forward, the field must develop validated biomarkers of choline adequacy in free-living populations, harmonize intervention protocols, and define context-specific requirements across obesity, pregnancy, and glucagon-like peptide-1 (GLP-1)-based therapy use. These efforts will refine dietary recommendations and solidify choline's role in lifelong brain and metabolic health.},
}

Humans
*Choline/metabolism/administration & dosage
Pregnancy
*Cardiovascular Diseases/prevention & control/metabolism
Female
Brain/metabolism/drug effects
Cognition/drug effects
Obesity/metabolism
Methylamines/metabolism
Animals
Dietary Supplements

@article {pmid41305589,
year = {2025},
author = {Wiciński, M and Fajkiel-Madajczyk, A and Wójcicki, J and Ozorowski, M and Szambelan, M},
title = {The Role of Bacopa monnieri in Alzheimer's Disease: Mechanisms and Potential Clinical Use-A Review.},
journal = {Nutrients},
volume = {17},
number = {22},
pages = {},
doi = {10.3390/nu17223538},
pmid = {41305589},
issn = {2072-6643},
mesh = {*Bacopa/chemistry ; *Alzheimer Disease/drug therapy ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Plant Extracts/pharmacology/therapeutic use ; Animals ; Medicine, Ayurvedic ; Phytotherapy ; Antioxidants/pharmacology ; },
abstract = {Over the past few years, there has been a growing interest in traditional Ayurvedic medicine, which extensively utilizes plants. One such plant is Bacopa monnieri, also known as brahmi, which has gained particular popularity for its cognitive-function-enhancing properties and neuroprotective effects. Numerous studies highlight its antioxidant, anti-inflammatory, anti-stress, anti-anxiety, and even symptom-reducing properties associated with attention deficit-hyperactivity disorder (ADHD). Additionally, in vitro and in vivo studies demonstrate the potential therapeutic applications of this plant and its active compounds, particularly bacosides, in treating Alzheimer's disease. This review aims to evaluate whether B. monnieri can serve as a potential therapy enhancer and slow the progression of Alzheimer's disease. We have attempted to clarify the mechanisms of action and the possible clinical application of brahmi in this progressive neurodegenerative brain disorder.},
}

*Bacopa/chemistry
*Alzheimer Disease/drug therapy
Humans
*Neuroprotective Agents/pharmacology/therapeutic use
*Plant Extracts/pharmacology/therapeutic use
Animals
Medicine, Ayurvedic
Phytotherapy
Antioxidants/pharmacology

@article {pmid41304975,
year = {2025},
author = {Abduljawad, AA and Alkinani, KB and Zaakan, A and AlGhamdi, AS and Hamdoon, AAE and Alshanbari, BH and Alshehri, AA and Alluhaybi, BB and Alqashi, SOI and Abduljawad, RA},
title = {Targeting Amyloid-β Proteins as Potential Alzheimer's Disease Therapeutics: Anti-Amyloid Drug Discovery, Emerging Therapeutics, Clinical Trials and Implications for Public Health.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {11},
pages = {},
doi = {10.3390/ph18111731},
pmid = {41304975},
issn = {1424-8247},
abstract = {Alzheimer's disease (AD), a neurodegenerative disorder of the aging brain, is associated with behavioral and cognitive issues and poses a huge burden on the global health care system. One of the key features of AD is the deposition of abnormal proteins called amyloid-beta (Aβ) in the brain, causing inflammatory changes, oxidative stress, and neuronal loss. Recent advancements in the anti-Aβ therapies have considerably improved the management of AD, resulting in better clinical outcomes for patients and caregivers. This review offers an inclusive update on current drug discovery efforts, innovative approaches, and ongoing clinical trials targeting Aβ, a key player in AD pathogenesis. We have evaluated the most recent developments in monoclonal antibodies, including aducanumab (discontinued November 2024), lecanemab, and donanemab, emerging therapeutic options, as well as emerging strategies such as tau-targeting therapies, gene therapy, and small molecule inhibitors. Moreover, we highlighted the challenges and opportunities in AD research, including the need for early diagnosis, personalized medicine, and combination therapies. Our review will offer a concise and informative overview of the current landscape and future directions in anti-Aβ therapeutics for AD, shedding light on potential treatments and prospects for improving patient outcomes.},
}

@article {pmid41304967,
year = {2025},
author = {Akantibila, M and Carabetta, VJ},
title = {Sirtuins as Therapeutic Targets for Treating Cancer, Metabolic Diseases, and Neurodegenerative Diseases.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {11},
pages = {},
doi = {10.3390/ph18111723},
pmid = {41304967},
issn = {1424-8247},
support = {R35GM138303/GM/NIGMS NIH HHS/United States ; },
abstract = {Sirtuins are NAD[+]-dependent enzymes that are conserved in all domains of life, including mammals, metazoans, plasmodia, yeast, bacteria, and archaea. In humans, there are seven isoforms (SIRT1 to 7), and they function in cellular homeostasis, aging, DNA repair, survival, metabolism, and stress responses. Recent advances highlight the diverse functions of sirtuins in the pathogenesis and progression of cancer, metabolic diseases, and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). To date, there is evidence that all seven isoforms contribute to cancer development, while SIRT1-3 and 6 contribute to metabolic and neurodegenerative diseases. Modulators of sirtuin activity are being actively explored to understand their biological and molecular mechanisms and potential for the treatment of various diseases. In this review, we begin with a broad discussion of post-translational modifications, protein deacetylation, and the mechanism of action of sirtuins. Next, we discuss the role of sirtuins in cancer, including inhibitors and activators of sirtuin activity as cancer therapies. In addition, we discuss the relationship of sirtuins to metabolic diseases and as possible treatment targets. Finally, we discuss the role of sirtuins in AD, PD, and HD, and sirtuin modulators for treating neurodegenerative diseases.},
}

@article {pmid41304943,
year = {2025},
author = {Saso, L and Ates, I and Tunc, R and Yilmaz, B and Gallorini, M and Carradori, S and Suzen, S},
title = {Modulation of Nrf2 and Mitochondrial Function: Pharmacological Implications.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {11},
pages = {},
doi = {10.3390/ph18111698},
pmid = {41304943},
issn = {1424-8247},
abstract = {Mammalians are constantly exposed to exogenous and endogenous sources of free radicals that have both favorable and harmful effects on the cellular systems. Oxidative stress (OS) is an imbalance of reactive oxygen species (ROS) and antioxidants in the body that can lead to serious cell damage. It is associated with many diseases such as cancer, Alzheimer's disease and heart disease. Background/Objectives: The Nuclear factor-2 erythroid-related factor-2 (Nrf2) is a transcription factor that controls the cellular oxidation state using antioxidant systems in the body and affects mitochondrial activities. Increased Nrf2 levels serve to protect cells from mitochondrial toxins; however, Nrf2 activity is inhibited in mitochondria-related diseases. In addition, Nrf2 is involved in mitochondrial activities for OS control. Methods: As mitochondrial wellbeing and activity is the chief controller for cellular metabolism, Nrf2 is a critical regulator for metabolic pathways. Thus, Nrf2 is the chief organizer of protection against OS in the cells. Nrf2 activator molecules support mitochondrial activity by stimulating mitophagy and helping to battle OS-related permeability transition. Conclusions: This review describes the influence of Nrf2 on OS and the way Nrf2 modulates mitochondrial function. Furthermore, we highlight recent studies of Nrf2 regarding its possible role in cell systems as well as pharmacological implications. Furthermore, this review emphasizes the importance of the mitochondria in the development of life-threatening diseases; pharmacological activation of Nrf2 is an important strategy to counter mitochondrial dysfunction.},
}

@article {pmid41304930,
year = {2025},
author = {Almaghrabi, M},
title = {Multitarget-Directed Ligands for Alzheimer's Disease: Recent Novel MTDLs and Mechanistic Insights.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {11},
pages = {},
doi = {10.3390/ph18111685},
pmid = {41304930},
issn = {1424-8247},
support = {447-13-1011//Taibah University/ ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, affecting millions of people and challenging the public health framework globally. While the definitive cause of AD remains unclear, researchers are concentrating their efforts on several prominent theories. Currently, there are very few FDA-approved medications for AD, and these primarily alleviate symptoms rather than alter the disease's progression. In response, research efforts focus on developing new medicines that address the complex nature of AD through multi-targeted approaches. Multitarget-directed ligands (MTDLs) are a promising treatment strategy for AD, despite the significant challenges they pose. This review examines recent advancements in designing prospective targeted MTDLs to combat AD, with a focus on categorizing the lead generation process and investigating the integration methods of key pharmacophores within the 2024-2025 timeframe. The review highlights numerous examples of novel MTDLs that address various AD hallmarks, demonstrating their broad therapeutic potential. These targets and activities include cholinesterase (AChE and/or BuChE) inhibition, monoamine oxidase (MAO-A and/or MAO-B) inhibition, antioxidant activity, amyloid-beta (Aβ) aggregation inhibition, tau protein aggregation inhibition, glycogen synthase kinase 3β (GSK-3β) inhibition, calcium channel blockade, anti-inflammatory activity, and other hallmarks.},
}

@article {pmid41304925,
year = {2025},
author = {Leichtweis, K and Predes, D and Mangelli, MC and Mauricio, H and de Jesus, BSM and Charlier, CF and da Silva, RC and Passos, GF and Oliveira, LFS and Nogueira, CO and Cavalcante, SFA and Lopes, DM and Almeida, RS and Bonfim, DC and Simas, ABC and R Clarke, J and Pinheiro, PSM and Abreu, JG},
title = {Exploring the Impact of 3-O-Methylquercetin on Wnt/β-Catenin Pathway Activity and Its Potential in Neural Processes.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {11},
pages = {},
doi = {10.3390/ph18111680},
pmid = {41304925},
issn = {1424-8247},
support = {E-26/200.936/2022 (268462)//FAPERJ/ ; E-26/210.055/2020 (250594)//FAPERJ/ ; SEI-260003/006052/2024//FAPERJ/ ; SEI-260003/004503/2025//FAPERJ/ ; E-26/211.598/2021//FAPERJ/ ; 309241/2007-3//CNPq/ ; 402176/2024-3//INCT/INOFAR/ ; },
abstract = {Background: The Wnt/β-catenin signaling pathway plays a pivotal role in embryonic development, maintenance of the central nervous system, and the formation of neuronal circuits. Disruption of this pathway is closely associated with oncogenesis and neurodegenerative diseases, notably Alzheimer's disease. Flavonoids such as quercetin derivatives have emerged as promising neuroprotective agents. This study investigates the impact of 3-O-methylquercetin (3OMQ), a methylated quercetin metabolite, on Wnt/β-catenin signaling and its potential relevance in neurodegenerative disease models. Methods: The ability of 3OMQ to modulate Wnt/β-catenin activity was analyzed using a luciferase-based reporter assay in both neural and non-neural cell lines. Cell viability assays evaluated cytotoxicity at various concentrations. We mapped 3OMQ activity within the pathway using targeted cell signaling experiments. Docking and molecular dynamics simulations suggested glycogen synthase kinase 3β (GSK3β) as a putative target of 3OMQ. Finally, we employed a mouse model of acute amyloid-β oligomer (AβO) toxicity to assess the in vivo effects of 3OMQ on spatial memory and Wnt-related gene expression. Results: We compared the flavonoids quercitrin, quercetin, and 3-O-methylquercitrin (3OMQ) with pharmacologically active compounds in a gene reporter assay (TOPFLASH) using Wnt-sensitive RKO cells treated with Wnt3a-conditioned medium. XAV-939 and PNU-74654 showed inhibitory activity, while BIO, CHIR99021, quercitrin, and 3OMQ enhanced the Wnt/β-catenin pathway. Notably, 3OMQ potentiated this pathway at concentrations 5-10 times lower than quercitrin and outperformed 1 μM BIO at 10 μM without cytotoxicity, highlighting its remarkable potency. Mechanistically, 3OMQ acts downstream of initial membrane activation and upstream of the β-catenin destruction complex. Consistently, molecular docking indicates a strong interaction with GSK3, a central regulator of the pathway. In adult mice, 3OMQ administration prevented AβO-induced recognition memory deficits and favored normalization of Wnt-related gene expression. Conclusions: These findings identify 3OMQ as a potent positive modulator of the Wnt/β-catenin pathway, with both in vitro and in vivo neuroprotective effects. Targeting Wnt signaling with compounds such as 3OMQ holds promise for maintaining neuronal health and developing therapeutic strategies for neurodegenerative conditions.},
}

@article {pmid41304756,
year = {2025},
author = {Jang, S and Kim, S and Kim, NH and Shin, SJ and Kumar, V and Son, JG and Lee, M and Kim, CG and Lim, EK and Chung, H and Koh, YH and Nam, Y and Moon, M},
title = {Amodiaquine Modulates Aggregation and Disassembly of Amyloid-β and Tau and Attenuates Neuroinflammatory Responses and Aβ Production.},
journal = {Pharmaceutics},
volume = {17},
number = {11},
pages = {},
doi = {10.3390/pharmaceutics17111417},
pmid = {41304756},
issn = {1999-4923},
support = {RS-2024-00450135//National Research Foundation of Korea/ ; 2025-RISE-06-001//Regional Innovation System & Education (RISE) program through the Daejeon RISE Center/ ; },
abstract = {Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles, which synergistically accelerate disease progression. Since Aβ plaques and tau tangles are key factors in the development of AD, dual-targeting of Aβ and tau aggregation represents a promising therapeutic strategy. Amodiaquine (AQ), a quinoline-based antimalarial, has recently attracted attention for its ability to suppress protein aggregation. However, direct effects of AQ on both Aβ and tau aggregation remain unclear. Methods: The effects of AQ on the aggregation and dissociation of Aβ and tau were examined using a thioflavin T (ThT) assays. Molecular docking and molecular dynamics (MD) simulations were performed to examine binding characteristics and structural interactions. The effects of AQ on the expression of pro-inflammatory cytokines induced by Aβ and tau aggregation in BV2 microglial cells were analyzed by qRT-PCR. Results: ThT assay demonstrated a dose-dependent dual effect of AQ on Aβ, where 25 μM inhibited aggregation after 36 h, while 250 μM markedly accelerated it, reaching a plateau within 12 h. All concentrations of AQ promoted the disassembly of mature Aβ fibrils within 12 h. Molecular docking revealed stronger binding of AQ to aggregated Aβ (-45.17 and -23.32 kcal/mol for pentameric 2BEG and hexameric 2NAO) than to monomeric Aβ (-4.81 and -7.29 kcal/mol for 1Z0Q and 2BEG). MD simulation suggested that AQ disrupted the cross-β-sheet interactions of Aβ aggregates. In the case of tau, ThT assay showed that all concentrations of AQ inhibited tau aggregation from 6 h, and 350 μM AQ promoted the disassembly of mature fibrils from 6 h. Molecular docking indicated stronger binding of AQ to aggregated tau (-27.95 and -12.13 kcal/mol for the pentameric and decameric 5O3L) than to monomeric tau (-3.05 kcal/mol for 8Q96). MD simulations revealed no major structural changes in the aggregates. In BV2 cells, 1 and 10 μM AQ significantly reduced Aβ and tau-induced TNF-α and IL-6 mRNA expressions. In APP-H4 cells, 10 μM AQ decreased the level of Aβ compared to the control. Conclusions: AQ modulates both Aβ and tau aggregation and attenuates neuroinflammation and reduces Aβ pathology, supporting its potential as a dual-target therapeutic candidate for AD.},
}

@article {pmid41304645,
year = {2025},
author = {Aly, SH and Sung Lee, G and Jang, YS and Fayez, S and Kim, KH and Kim, CS and El-Shazly, M},
title = {Chemical Profiling of Gmelina philippensis Cham. Leaf Extract and Its Antioxidant and Anti-Cholinesterase Properties.},
journal = {Plants (Basel, Switzerland)},
volume = {14},
number = {22},
pages = {},
doi = {10.3390/plants14223494},
pmid = {41304645},
issn = {2223-7747},
support = {RS-2019-NR040057, RS-2021-NR059240//National Research Foundation of Korea (NRF)/ ; },
abstract = {Gmelina philippensis Cham. (Lamiaceae) is a traditionally valued medicinal plant with unexplored potential for the management of neurodegenerative disorders. In the present study, the phytochemical profile of its methanolic leaf extract was comprehensively characterized using untargeted liquid chromatography-tandem mass spectrometry metabolomics (LC-MS/MS) and molecular networking. In addition, the extract was evaluated for its antioxidant and cholinesterase inhibitory activities relevant to Alzheimer's disease (AD). Metabolite profiling led to the annotation of 27 compounds, with a predominance of flavonoids and iridoid glycosides unique to the genus Gmelina, along with phenolic acids, lipids, and other minor compounds. The extract exhibited potent in vitro antioxidant activity, with an IC50 of 7.49 ± 0.002 μg/mL in the DPPH assay and 639.63 ± 0.814 μg AAE/mg in the FRAP assay. Notably, the extract showed significant inhibitory activity against acetylcholinesterase and butyrylcholinesterase, with an IC50 of 4.87 ± 0.16 and 40.99 ± 0.03 μg/mL, respectively. Molecular networking further supported the metabolite annotation and highlighted clusters of bioactive iridoids and flavonoids. Overall, these findings highlight that G. philippensis as a rich source of multi-target bioactive compounds, supporting that the extract has good anti-acetylcholinesterase activity comparable to the rivastigmine that used in neurodegenerative disease. This study provides a promising foundation for the development of novel therapeutic approaches targeting neurodegenerative diseases.},
}

@article {pmid41304419,
year = {2025},
author = {Ezzaki, C and Chaari, A and Al-Othman, A},
title = {Recent Advances on Chitosan-Based Nanoparticles for Brain Drug Delivery.},
journal = {Polymers},
volume = {17},
number = {22},
pages = {},
doi = {10.3390/polym17223055},
pmid = {41304419},
issn = {2073-4360},
abstract = {The blood-brain barrier (BBB) represents a major challenge in effective drug delivery systems intended for treating neurological disorders. It restricts the transport of therapeutic agents to the brain. Chitosan-based nanoparticles (CNPs) can be used for brain drug delivery because of their biocompatibility, biodegradability, and ability to enhance drug permeability across the BBB. This review article discusses the design and application of CNPs for brain-targeted drug delivery, exploring their mechanisms of action, including adsorptive-mediated and receptor-mediated endocytosis. Surface modifications with ligands such as chlorotoxin are discussed for improving specificity and therapeutic results. Findings show that CNPs allow controlled drug release, enhance stability, and reduce side effects, which make them effective for treating multiple neurological conditions, including Alzheimer's disease, Parkinson's disease, brain tumors, and ischemic stroke. CNPs can encapsulate multiple therapeutic agents, such as anti-inflammatory drugs, cytotoxic agents, and genetic materials, and maintain stability under different physiological conditions. Intranasal delivery routes are mainly discussed in this paper for their ability to bypass systemic circulation and achieve direct brain targeting. This review also addresses challenges such as cytotoxicity and the need for optimizing nanoparticle size, charge, and surface properties to improve the therapy results. While CNPs are suitable for brain drug delivery, there is a research gap, which is the lack of systematic studies evaluating their long-term effects on brain tissue and health. Most studies focus on acute therapeutic outcomes and in vitro or short-term in vivo analysis, which do not address some questions about the chronic exposure risks, biodistribution, and clearance pathways of CNPs. This review also explores the use of chitosan-based nanoparticles to deliver drugs to the brain for the treatment of multiple neurological disorders.},
}

@article {pmid41303831,
year = {2025},
author = {Uehara, MA and Kalia, S and Garcia Campuzano, M and Moussavi, Z},
title = {ADAS-Cog Trajectories Differ from Expected Decline in Dementia Following Repeated Non-Invasive Interventions over 3 Years.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {61},
number = {11},
pages = {},
doi = {10.3390/medicina61111994},
pmid = {41303831},
issn = {1648-9144},
support = {RGPIN-2023-04308//Natural Sciences and Engineering Research Council of Canada/ ; IT43832//Mitacs/ ; },
mesh = {Humans ; Male ; Female ; Aged ; *Dementia/therapy/psychology ; Aged, 80 and over ; Transcranial Magnetic Stimulation/methods ; *Cognitive Dysfunction/therapy ; Disease Progression ; Alzheimer Disease/therapy/psychology ; Longitudinal Studies ; Neuropsychological Tests ; Middle Aged ; Mental Status and Dementia Tests ; },
abstract = {Background and Objectives: Non-pharmaceutical interventions such as cognitive training, transcranial electrical stimulation (tES), and repetitive transcranial magnetic stimulation (rTMS) have shown promise in improving cognitive outcomes in Alzheimer's disease (AD) and dementia. However, the long-term effects of repeated non-invasive interventions remain unknown. This study investigated whether repeated non-invasive interventions administered over a span of 1 to 3 years were associated with slower cognitive decline compared to typical AD progression, and whether longer no-treatment intervals between treatments predicted greater post-treatment decline. Materials and Methods: Seventy-three participants living with dementia or AD received 2 to 9 blocks of non-invasive treatments (including tES, rTMS, cognitive training). Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores were collected longitudinally up to 3 years (36 months), across multiple intervention and assessment sessions. A mixed-effects model was used to estimate the rate of cognitive decline, adjusting for baseline age, sex, and baseline cognition (MoCA) with participants being the random effect. The observed rate of change was compared to a meta-analysis estimate of AD progression. Additionally, a linear mixed-effects model using robust sandwich estimation of standard errors was employed to assess whether the no-treatment interval was associated with changes in ADAS-Cog scores. Results: Participants showed a significantly slower rate of cognitive decline than expected from the AD reference rate (p < 0.001), with many demonstrating stabilized ADAS-Cog scores during their respective treatment periods, ranging from 1 to 3 years. Medication analyses revealed no significant effect of AD medications, antidepressants, antihypertensives, or cholesterol-lowering agents on cognitive outcomes. Furthermore, longer no-treatment intervals were significantly associated with greater post-treatment decline (p < 0.001). Conclusions: Repeated non-invasive treatments seem to slow the rate of cognitive decline in individuals living with dementia when administered over a prolonged period. This study provides evidence supporting the feasibility and effects of personalized long-term non-invasive treatment strategies for dementia.},
}

Humans
Male
Female
Aged
*Dementia/therapy/psychology
Aged, 80 and over
Transcranial Magnetic Stimulation/methods
*Cognitive Dysfunction/therapy
Disease Progression
Alzheimer Disease/therapy/psychology
Longitudinal Studies
Neuropsychological Tests
Middle Aged
Mental Status and Dementia Tests

@article {pmid41303755,
year = {2025},
author = {Chang, J},
title = {EEG Microstate Differences Between Alzheimer's Disease, Frontotemporal Dementia, and Healthy Controls Using 4 and 7 Clustering Classes with a Ratio Approach.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {61},
number = {11},
pages = {},
doi = {10.3390/medicina61111917},
pmid = {41303755},
issn = {1648-9144},
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnosis/classification ; *Frontotemporal Dementia/physiopathology/diagnosis/classification ; Male ; *Electroencephalography/methods ; Female ; Aged ; Middle Aged ; Cluster Analysis ; Case-Control Studies ; Mental Status and Dementia Tests ; Diagnosis, Differential ; },
abstract = {Background and Objectives: Alzheimer's disease (AD) and frontotemporal dementia (FTD) present overlapping clinical and neuroanatomical features, complicating early diagnosis. Therefore, this study evaluated whether EEG microstate analysis can provide reliable markers to distinguish patients with dementia from healthy controls. Materials and Methods: Resting-state EEG was recorded from 36 AD patients, 23 FTD patients, and 29 healthy controls. Preprocessing and microstate analysis were conducted using the MICROSTATELAB pipeline in EEGLAB. Clustering solutions ranging from four to seven classes were tested, with grand mean fitting and variance thresholds. Temporal parameters (duration, occurrence, and coverage) and their ratio-normalized forms were compared across groups using ANCOVA and nonparametric tests. Associations with Mini-Mental State Examination (MMSE) scores were assessed by regression analyses. Results: The four- and seven-class clustering solutions achieved high variance overlap with published microstate templates. In the four-class solution, temporal parameters of microstates B and D significantly differentiated controls from dementia groups, while in the seven-class solution, microstates C and G were the most informative. Ratio-normalized parameters improved group discrimination and were associated with MMSE scores. Conclusions: EEG microstates capture disease-related alterations in large-scale brain dynamics that differentiate patients with dementia from healthy individuals.},
}

Humans
*Alzheimer Disease/physiopathology/diagnosis/classification
*Frontotemporal Dementia/physiopathology/diagnosis/classification
Male
*Electroencephalography/methods
Female
Aged
Middle Aged
Cluster Analysis
Case-Control Studies
Mental Status and Dementia Tests
Diagnosis, Differential

@article {pmid41303651,
year = {2025},
author = {Arnaldo, L and Mena, J and Adamuz, D and Menéndez, A and Serradell, M and Samaniego, D and Gaig, C and Ispierto, L and Vilas, D and Iranzo, A and Aarsland, D and Pastor, P and Beyer, K},
title = {Does Platelet Transcriptome Dysregulation Across the Lewy Body Continuum Mirror Neuronal Dysfunction?.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262211169},
pmid = {41303651},
issn = {1422-0067},
support = {PI21/00833, PI21/00886, PMP22/00100, PI24/00214//Ministerio de Ciencia, Innovación y Universidades/ ; },
mesh = {Humans ; *Blood Platelets/metabolism ; *Lewy Body Disease/genetics/pathology/blood/metabolism ; *Transcriptome/genetics ; Male ; Aged ; Female ; Parkinson Disease/genetics/pathology ; Alzheimer Disease/genetics/pathology ; Gene Expression Profiling ; RNA, Long Noncoding/genetics ; Aged, 80 and over ; *Lewy Bodies/metabolism/pathology ; REM Sleep Behavior Disorder/genetics ; *Neurons/metabolism/pathology ; Gene Expression Regulation ; RNA, Messenger/genetics ; Platelet Activation/genetics ; Middle Aged ; },
abstract = {Platelets are increasingly recognized as multifunctional cells with roles extending beyond hemostasis to immune regulation, inflammation, and neurodegeneration. Here, we performed RNA-Seq profiling of platelets from patients with idiopathic REM sleep behavior disorder (IRBD), dementia with Lewy bodies (DLB), Parkinson disease (PD), Alzheimer disease (AD), and healthy controls (CTRLs) to explore disease-specific transcriptomic signatures. Across all groups, the RNA class distribution was similar, dominated by mRNAs (78-80%) and long non-coding RNAs (lncRNAs; 15-16%). DLB platelets displayed a reduced proportion of lncRNAs, suggesting an impaired RNA regulation, whereas IRBD concentrated the highest number of disease-specific lncRNAs, half of which were Y-linked, consistent with the male predominance observed in alpha-synucleinopathies. Differential expression analysis (DEA) revealed extensive transcriptomic remodeling in IRBD and DLB, particularly affecting RNA processing, cytoskeletal organization, and platelet activation pathways, while PD and AD showed minimal changes. These findings suggest a progressive impairment of platelet activation and signaling across the DLB continuum, potentially mirroring neuronal dysfunction. The limited transcriptional deregulation in PD may reflect its pronounced biological heterogeneity, consistent with recent multidimensional disease models. Overall, our study highlights platelets as accessible indicators of early and disease-stage-specific molecular alterations in α-synucleinopathies.},
}

Humans
*Blood Platelets/metabolism
*Lewy Body Disease/genetics/pathology/blood/metabolism
*Transcriptome/genetics
Male
Aged
Female
Parkinson Disease/genetics/pathology
Alzheimer Disease/genetics/pathology
Gene Expression Profiling
RNA, Long Noncoding/genetics
Aged, 80 and over
*Lewy Bodies/metabolism/pathology
REM Sleep Behavior Disorder/genetics
*Neurons/metabolism/pathology
Gene Expression Regulation
RNA, Messenger/genetics
Platelet Activation/genetics
Middle Aged

@article {pmid41303637,
year = {2025},
author = {Rodríguez-Pozo, M and Pacheco-Sánchez, B and Ben Rabaa, M and de Ceglia, M and Melgar-Locatelli, S and Santos, I and Rodríguez de Fonseca, F and Suárez, J and Rivera, P},
title = {Perinatal Ethanol Exposure Induces Astrogliosis and Decreases GRP55/PEA-Mediated Neuroprotection in Hippocampal Astrocytes of the 3×Tg Alzheimer's Animal Model.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262211154},
pmid = {41303637},
issn = {1422-0067},
support = {RYC2023-044921-I//MCIU/AEI/10.13039/501100011033 and the FSE+./ ; 2020/048//Ministerio de Sanidad, Delegación de Gobierno para el Plan Nacional sobre Drogas/ ; PI21/00291//Consejería de Universidad, Investigación e Innovación, Junta de Andalucía/ ; IFI21/00024//National System of Health, EU-ERDF-ISCIII./ ; CD24/00124//Instituto de Salud Carlos III/ ; PT23/00082//Plataforma ISCIII de Dinamización e Innovación de las capacidades industriales del SNS y su transferencia efectiva al sector productivo/ ; DTS22/00021//Proyectos Desarrollo Tecnológico ISCIII/ ; P18-TP-5194//Proyectos Tractores Junta De Andalucia/ ; },
mesh = {Animals ; *Astrocytes/metabolism/drug effects/pathology ; *Ethanol/adverse effects/toxicity ; *Hippocampus/metabolism/pathology/drug effects ; *Alzheimer Disease/metabolism/pathology/genetics ; Female ; Pregnancy ; Disease Models, Animal ; Male ; *Gliosis/metabolism/pathology/chemically induced ; Mice ; *Prenatal Exposure Delayed Effects/metabolism/pathology ; *Neuroprotection/drug effects ; Mice, Transgenic ; Cells, Cultured ; Receptors, Cannabinoid/metabolism ; },
abstract = {Prenatal ethanol exposure (PEE) alters fetal brain development, potentially increasing the risk of neurodegenerative diseases such as Alzheimer's disease (AD) later in life. Although glial activation is implicated in AD pathology via cannabinoid and neuroinflammatory signaling, its potential response to PEE in the developing brain and its contribution to AD pathogenesis remain unknown. Using 3×Tg-AD offspring of both sexes born to mothers with PEE, we analyzed astrogliosis, inflammatory markers, and key components of cannabinoid and Ca[2+] signaling in primary cultures of hippocampal astrocytes, elements whose dysfunction contributes to neurodegeneration. Our results indicated that PEE increased astrogliosis/inflammatory response (significant elevation of Gfap and Tnfα expression) in hippocampal astrocytes at birth. This neuroinflammation was significantly associated with lower expression of cannabinoid receptors (Cnr1 and Gpr55), and decreased concentrations of the anti-inflammatory lipid PEA in the culture medium, probably due to a deregulated endocannabinoid enzymatic machinery (NAPE-PLD/FAAH ratio). This research provides insights into GRP55/PEA-mediated signaling as a potential hippocampal astrocytic mechanism influenced by maternal ethanol exposure, which may contribute to neurobiological changes associated with increased vulnerability to AD-related pathology.},
}

Animals
*Astrocytes/metabolism/drug effects/pathology
*Ethanol/adverse effects/toxicity
*Hippocampus/metabolism/pathology/drug effects
*Alzheimer Disease/metabolism/pathology/genetics
Female
Pregnancy
Disease Models, Animal
Male
*Gliosis/metabolism/pathology/chemically induced
Mice
*Prenatal Exposure Delayed Effects/metabolism/pathology
*Neuroprotection/drug effects
Mice, Transgenic
Cells, Cultured
Receptors, Cannabinoid/metabolism

@article {pmid41303587,
year = {2025},
author = {Kononova, SV and Bobkova, NV and Poltavtseva, RA and Leonov, S and Sukhikh, GT},
title = {ACE2: Friend or Foe in Post-COVID-19 Neurodegeneration?.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262211104},
pmid = {41303587},
issn = {1422-0067},
support = {24-25-00465//Russian Science Foundation/ ; },
mesh = {Humans ; *Angiotensin-Converting Enzyme 2/metabolism ; *COVID-19/complications/metabolism/virology ; SARS-CoV-2/metabolism ; *Neurodegenerative Diseases/metabolism/etiology/virology ; Spike Glycoprotein, Coronavirus/metabolism ; Renin-Angiotensin System ; Animals ; Alzheimer Disease/metabolism ; Brain/metabolism/pathology/virology ; },
abstract = {Angiotensin-converting enzyme 2 (ACE2) is a key component of the renin-angiotensin system's counter-regulatory pathway. ACE2 is a multifunctional protein whose location and form determine its catalytic and non-catalytic functions, including amino acid transport, the creation of structural complexes, adhesion, and involvement in signaling pathways. In addition, ACE2 influences neurotransmitter systems in the brain. As the main receptor for SARS-CoV-2, ACE2 has been the subject of increasing research interest. Although ACE2 levels in the brain are low, brain damage from SARS-CoV-2 increases the risk of neurodegenerative diseases. This review aims to clarify an important issue: does the temporary inactivation of ACE2 by the SARS-CoV-2 spike protein play a role in Alzheimer-like neurodegeneration, meaning that the protein may serve as a biomarker or therapeutic target?},
}

Humans
*Angiotensin-Converting Enzyme 2/metabolism
*COVID-19/complications/metabolism/virology
SARS-CoV-2/metabolism
*Neurodegenerative Diseases/metabolism/etiology/virology
Spike Glycoprotein, Coronavirus/metabolism
Renin-Angiotensin System
Animals
Alzheimer Disease/metabolism
Brain/metabolism/pathology/virology

@article {pmid41303552,
year = {2025},
author = {Volbracht, C and Fog, K},
title = {Deubiquitinating Enzymes Ubiquitin-Specific Proteases 7 and 10 Regulate TAU Aggregation.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262211062},
pmid = {41303552},
issn = {1422-0067},
mesh = {*tau Proteins/metabolism ; Animals ; *Ubiquitin Thiolesterase/metabolism/genetics/antagonists & inhibitors ; *Ubiquitin-Specific Peptidase 7/metabolism/genetics/antagonists & inhibitors ; Mice ; Ubiquitination ; Neurons/metabolism ; Hippocampus/metabolism ; Alzheimer Disease/metabolism/pathology ; Humans ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates ; },
abstract = {Accumulation of the microtubule-associated protein TAU into inclusions is a hallmark of tauopathies including Alzheimer's disease (AD), potentially driven by impaired protein degradation and dysregulated ubiquitination. To explore the role of deubiquitinating enzymes (DUBs), we performed siRNA knockdown screens targeting 93 murine DUBs in rTg4510 cortical cultures. Knockdown and pharmacological inhibition of the ubiquitin-specific proteases 7 (Usp7) and 10 (Usp10) significantly reduced seeded TAU aggregation without affecting soluble TAU levels. These effects were observed in both cortical and organotypic hippocampal slice cultures from rTg4510 mice, as well as in wildtype neurons seeded with AD-derived pathological TAU. Inhibition of Usp7 and Usp10 was associated with increased polyubiquitination of residual TAU inclusions in rTg4510 cortical cultures. These findings suggest that Usp7 and Usp10 contribute to pathological TAU accumulation by modulating ubiquitin-dependent degradation pathways. Targeting USP7 and USP10 may offer a novel therapeutic strategy for AD and related tauopathies.},
}

*tau Proteins/metabolism
Animals
*Ubiquitin Thiolesterase/metabolism/genetics/antagonists & inhibitors
*Ubiquitin-Specific Peptidase 7/metabolism/genetics/antagonists & inhibitors
Mice
Ubiquitination
Neurons/metabolism
Hippocampus/metabolism
Alzheimer Disease/metabolism/pathology
Humans
*Protein Aggregation, Pathological/metabolism
Protein Aggregates

@article {pmid41303517,
year = {2025},
author = {Oporto-Colicoi, V and Sepúlveda-Lara, A and Marzuca-Nassr, GN and Sepúlveda-Figueroa, P},
title = {Mild Cognitive Impairment and Sarcopenia: Effects of Resistance Exercise Training on Neuroinflammation, Cognitive Performance, and Structural Brain Changes.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262211036},
pmid = {41303517},
issn = {1422-0067},
mesh = {Humans ; *Cognitive Dysfunction/therapy/physiopathology/pathology ; *Resistance Training/methods ; *Sarcopenia/therapy/physiopathology/pathology ; *Brain/pathology/physiopathology ; *Cognition/physiology ; *Neuroinflammatory Diseases/therapy ; Animals ; Inflammation ; },
abstract = {Mild cognitive impairment (MCI) and sarcopenia are prevalent age-related conditions that often coexist and share common mechanisms such as chronic inflammation, reduced neuroplasticity, and impaired muscle function. Resistance exercise training (RET) has emerged as a promising non-pharmacological strategy capable of addressing both physical and cognitive decline. The aim of this narrative review is to synthesize preclinical and clinical evidence on the effects of RET in older adults with MCI and sarcopenia, with a specific focus on its impact on neuroinflammation, cognitive performance and structural brain changes. At the molecular level, RET activates anabolic pathways, including PI3K/Akt/mTOR, enhances neurotrophic support via BDNF, NT-3, and IGF-1, and promotes hippocampal neurogenesis through exercise-induced myokines such as irisin and cathepsin B. RET also exerts immunomodulatory actions by shifting microglia toward anti-inflammatory M2 phenotypes, attenuating reactive astrogliosis, and supporting oligodendrocyte precursor cell differentiation, thereby improving myelin integrity. Neuroimaging studies consistently report preservation of hippocampal and precuneus gray matter, as well as improved white matter connectivity following RET. Clinically, RET has demonstrated significant and sustained improvements in executive function, memory, and global cognition, with effects persisting for up to 18 months. Collectively, RET represents a multifaceted intervention with the potential to delay progression from MCI to Alzheimer's disease by integrating neuroprotective, anti-inflammatory, and anabolic effects. Standardization of RET protocols and identification of biomarkers of responsiveness are needed to optimize its role within multimodal dementia-prevention strategies.},
}

Humans
*Cognitive Dysfunction/therapy/physiopathology/pathology
*Resistance Training/methods
*Sarcopenia/therapy/physiopathology/pathology
*Brain/pathology/physiopathology
*Cognition/physiology
*Neuroinflammatory Diseases/therapy
Animals
Inflammation

@article {pmid41303502,
year = {2025},
author = {Hassan, M and Shahzadi, S and Moustafa, AA and Kloczkowski, A},
title = {Neurodegeneration Through the Lens of Bioinformatics Approaches: Computational Mechanisms of Protein Misfolding.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262211021},
pmid = {41303502},
issn = {1422-0067},
support = {1R01HG012117-04/NH/NIH HHS/United States ; },
mesh = {Humans ; *Computational Biology/methods ; *Neurodegenerative Diseases/metabolism ; *Protein Folding ; Animals ; Protein Aggregates ; Protein Aggregation, Pathological/metabolism ; },
abstract = {Protein and peptide aggregation has become a prominent focus in biomedical research due to its critical role in the development of neurodegenerative diseases (NDs) and its relevance to industrial applications. Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are closely associated with abnormal aggregation processes, highlighting the need for a deeper understanding of their molecular mechanisms. In recent years, a wide range of computational methods, bioinformatics tools, and curated databases have been developed to predict and analyze sequences and structures that are prone to aggregation. These in silico approaches offer valuable insights into the underlying principles of aggregation and contribute to the identification of potential therapeutic targets. This review provides a concise overview of the current bioinformatics resources and computational techniques available for studying protein and peptide aggregation, intending to guide future research efforts in the field of neurodegenerative disease modeling and drug discovery.},
}

Humans
*Computational Biology/methods
*Neurodegenerative Diseases/metabolism
*Protein Folding
Animals
Protein Aggregates
Protein Aggregation, Pathological/metabolism

@article {pmid41303478,
year = {2025},
author = {Polishchuk, H and Guzik, K and Kantyka, T},
title = {Beyond Hunger: The Structure, Signaling, and Systemic Roles of Ghrelin.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210996},
pmid = {41303478},
issn = {1422-0067},
support = {UMO-2016/22/E/NZ5/00332//National Science Centre/ ; },
mesh = {*Ghrelin/metabolism/chemistry ; Humans ; *Signal Transduction ; Animals ; *Receptors, Ghrelin/metabolism/chemistry ; *Hunger/physiology ; },
abstract = {Our understanding of Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor 1a (GHSR1a), has expanded from considering it to be a "hunger hormone" to a pleiotropic regulator of whole-body physiology. This review synthesizes the current advances spanning ghrelin biogenesis, signaling, and systems biology. Physiologically, preproghrelin processing and O-acylation by ghrelin O-acyltransferase (GOAT) generate acyl-ghrelin, a high-potency GHSR1a agonist; des-acyl ghrelin predominates in circulation and exerts context-dependent, GHSR1a-independent, or low-potency effects, while truncated "mini-ghrelins" can act as competitive antagonists. The emergence of synthetic ligands, agonists, antagonists, and reverse-agonists has provided the necessary tools to decipher GHSR1a activity. Recent cryo-EM structures of GHSR1a with peptide and small-molecule ligands reveal a bipartite binding pocket and provide a framework for biased signaling, constitutive activity, and receptor partner selectivity. Beyond the regulation of feeding and growth-hormone release, ghrelin modulates glucose homeostasis, gastric secretion and motility, cardiovascular tone, bone remodeling, renal hemodynamics, and innate immunity. Ghrelin broadly dampens pro-inflammatory responses and promotes reparative macrophage phenotypes. In the emerging scholarship on ghrelin's activity in the central nervous system, ghrelin has been found to influence neuroprotection, stress reactivity, and sleep architecture, and has also been implicated in depression, Alzheimer's disease, and substance-abuse disorders. Practical and transitional aspects are also highlighted in the literature: approaches for ghrelin stabilization; recent GHSR1a agonists/antagonists and inverse agonists findings; LEAP-2-based strategies; and emerging GOAT inhibitors. Together, structural insights and pathway selectivity position the ghrelin system as a druggable axis for the management of inflammatory diseases, neuropsychiatric and addiction conditions, and for obesity treatment in the post-GLP-1 receptor agonist era.},
}

*Ghrelin/metabolism/chemistry
Humans
*Signal Transduction
Animals
*Receptors, Ghrelin/metabolism/chemistry
*Hunger/physiology

@article {pmid41303442,
year = {2025},
author = {Aliuș, C and Breazu, A and Pantu, C and Toader, C and Șerban, M and Covache-Busuioc, RA and Munteanu, O and Dumitru, AV},
title = {The Endocannabinoid-Microbiota-Neuroimmune Super-System: A Unifying Feedback Architecture for Systems Resilience, Collapse Trajectories, and Precision Feedback Medicine.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210959},
pmid = {41303442},
issn = {1422-0067},
mesh = {*Endocannabinoids/metabolism ; Humans ; Animals ; *Microbiota ; Feedback, Physiological ; *Precision Medicine/methods ; *Neuroimmunomodulation ; },
abstract = {Modern biomedicine frequently contextualizes disease around isolated molecular or organ-specific mechanisms, but numerous chronic diseases, including Alzheimer's disease, multiple sclerosis, depression, diabetes, and sepsis, share common trajectories of systemic destabilization. An increasing body of evidence indicates that health is not a property of single organs but the emergent property of interdependent feedback networks linking the microbiome, endocannabinoidome, neuroimmune system, and metabolic regulators. We propose the Endocannabinoid-Microbiota-Neuroimmune Super-System (EMN-S) as an evolutionarily conserved conceptual model that describes how these fields of influence reciprocally interact through feedback control. The microbial communities constituting the EMN-S encode environmental and dietary inputs, endocannabinoid signaling serves as an integrative regulator that synchronizes neural and immune activity, and neuroimmune circuits effectuate adaptive behaviors that alter microbiotal and lipid ecosystems. This review formalizes the EMN-S, contending that it is a unitary and cohesive model of physiological resilience, as well as offering a framework for precision feedback therapeutics. We describe how three mechanisms-encoder drift, integrator detuning, and executor overutilization-convert stabilizing negative feedback into runaway feedback cascades that underlie chronic, recurrent, and multisystemic disease. We then specify the EMN-S signature-integrated microbiome, lipidomic, and immune readouts-as an early indicator of resilience collapse and prospective preclinical state. Finally, we recapitulate the potential of AI-driven digital twins to illuminate feedback collapse, predict tipping points, and direct closed-loop intervention and treatments to restore dynamic equilibrium. By anchoring complexity in concrete and measurable feedback principles, the EMN-S shifts focus to investigate pathophysiology as opposed to reductionist lesion models of systemic derangements and embraces a systemic, empirically testable theory of stability.},
}

*Endocannabinoids/metabolism
Humans
Animals
*Microbiota
Feedback, Physiological
*Precision Medicine/methods
*Neuroimmunomodulation

@article {pmid41303432,
year = {2025},
author = {Lee, SY and Kim, JC and Choi, MR and Song, J and Kim, M and Chang, SH and Kim, JS and Park, JS and Lee, SR},
title = {KBN2202, a Salicylic Acid Derivative, Preserves Neuronal Architecture, Enhances Neurogenesis, Attenuates Amyloid and Inflammatory Pathology, and Restores Recognition Memory in 5xFAD Mice at an Advanced Stage of AD Pathophysiology.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210942},
pmid = {41303432},
issn = {1422-0067},
support = {RS-2023-00223559//National Research Foundation of Korea (NRF), funded by the Korean government (MSIT)/ ; RS-2023-00267453//Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea/ ; RS-2021-KH113822//Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea/ ; },
mesh = {Animals ; *Neurogenesis/drug effects ; *Alzheimer Disease/drug therapy/pathology/metabolism/physiopathology ; Doublecortin Protein ; Mice ; Amyloid beta-Peptides/metabolism ; *Neurons/drug effects/pathology/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Male ; *Memory/drug effects ; Amyloid beta-Protein Precursor/metabolism ; Inflammation/drug therapy/pathology ; Hippocampus/drug effects ; Neuroprotective Agents/pharmacology ; *Salicylic Acid/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β (Aβ) pathology, synaptic degeneration, impaired neurogenesis, and chronic neuroinflammation. KBN2202, a small-molecule salicylic acid derivative [2-[(2-naphthalen-1-yloxy)ethyl]amino]-4-hydroxybenzoic acid], was investigated for its potential as a multi-target therapeutic agent in advanced-stage AD. To this end, 9-month-old 5xFAD mice with established AD-like pathology received daily oral KBN2202 (5 or 20 mg/kg) or vehicle for 12 weeks. KBN2202 demonstrated broad histopathological benefits. It preserved hippocampal CA1 cytoarchitecture and increased dendritic length in cortical neurons. Neurogenic activity was also enhanced, with elevated doublecortin (DCX) expression in the subventricular zone (SVZ). At the molecular level, KBN2202 reduced amyloid precursor protein C-terminal fragments (APP-CTFs), key intermediates in amyloidogenic processing, and histological staining confirmed a significant reduction in fibrillar and diffuse Aβ plaque burden in the cortex and hippocampus. Furthermore, KBN2202 attenuated astrocytic and microglial activation, indicating suppression of chronic neuroinflammation. In behavioral assessments, KBN2202 significantly improved recognition memory in the novel object recognition (NOR) test, while Y-maze performance remained unchanged. Overall, the compound exhibited robust neuroprotective, pro-neurogenic, anti-amyloid, and anti-inflammatory effects. These findings support the therapeutic potential of KBN2202 as a multi-functional candidate for symptomatic-stage AD.},
}

Animals
*Neurogenesis/drug effects
*Alzheimer Disease/drug therapy/pathology/metabolism/physiopathology
Doublecortin Protein
Mice
Amyloid beta-Peptides/metabolism
*Neurons/drug effects/pathology/metabolism
Disease Models, Animal
Mice, Transgenic
Male
*Memory/drug effects
Amyloid beta-Protein Precursor/metabolism
Inflammation/drug therapy/pathology
Hippocampus/drug effects
Neuroprotective Agents/pharmacology
*Salicylic Acid/pharmacology

@article {pmid41303425,
year = {2025},
author = {Niño-Rivero, S and Cabral, R and Fleitas, J and Alcalde-Ahlig, L and Castaño, EM and Morelli, L and McGregor, R and Galeano, P and Lagos, P},
title = {Temporal Progression of Recognition Memory Impairment, Astrogliosis, and Cholinergic Dysfunction in the Streptozotocin Rat Model of Sporadic Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210944},
pmid = {41303425},
issn = {1422-0067},
support = {FCE_1_2017_1_136039//Agencia Nacional de Innovación e Investigación (ANII)/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/chemically induced/physiopathology ; Streptozocin/toxicity ; *Gliosis/pathology/metabolism ; Rats ; Disease Models, Animal ; *Memory Disorders/pathology/metabolism/physiopathology ; Male ; Hippocampus/pathology/metabolism ; Recognition, Psychology ; Rats, Wistar ; Disease Progression ; },
abstract = {The streptozotocin (STZ) experimental model of sporadic Alzheimer's disease (SAD), the most prevalent form of this type of dementia, has become a valuable tool to study the behavioral and morphological changes that occur during the gradual development of this pathology. We used the STZ experimental model in combination with the novel object recognition test (NORT) and immunohistochemical techniques to evaluate the recognition memory decline and morphological alterations in memory-related structures (hippocampus and cortex). Our analysis included five different time points after intracerebroventricular (ICV) administration of 3 mg/kg of STZ or artificial cerebrospinal fluid (aCSF) as a control. The time points included three distinct stages: early (15 and 30 days), intermediate (60 days), and late (90 and 120 days). We found that recognition memory impairment started in the intermediate stage and persisted through the later stages. Morphologically, we detected significant astrogliosis starting in the early stages, whereas cholinergic changes began in the intermediate stage. No neuronal loss was observed at any of the time points analyzed. Our results further support the hypothesis that astrogliosis constitutes an initial pathological event that may compromise the hippocampal cholinergic system and can contribute to the onset of recognition memory deficits.},
}

Animals
*Alzheimer Disease/pathology/metabolism/chemically induced/physiopathology
Streptozocin/toxicity
*Gliosis/pathology/metabolism
Rats
Disease Models, Animal
*Memory Disorders/pathology/metabolism/physiopathology
Male
Hippocampus/pathology/metabolism
Recognition, Psychology
Rats, Wistar
Disease Progression

@article {pmid41303365,
year = {2025},
author = {Faa, G and Meloni, C and Lastretti, M and Pinna, M and Manchia, M and Paribello, P},
title = {Perturbations of Zinc Homeostasis and Onset of Neuropsychiatric Disorders.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210877},
pmid = {41303365},
issn = {1422-0067},
mesh = {Humans ; *Zinc/metabolism ; *Homeostasis ; *Mental Disorders/metabolism/etiology ; Attention Deficit Disorder with Hyperactivity/metabolism ; Animals ; Schizophrenia/metabolism ; Depressive Disorder, Major/metabolism ; Alzheimer Disease/metabolism ; Autism Spectrum Disorder/metabolism ; Parkinson Disease/metabolism ; Bipolar Disorder/metabolism ; },
abstract = {Zinc (Zn[2+]) is a trace element essential for its catalytic, antioxidant, and immunomodulatory roles extending to synaptic signalling in the central nervous system. In this narrative review, we aim to offer the reader evidence linking perturbations of the Zn[2+] homeostasis, including deficiency, excess, or transportation anomalies, to neuropsychiatric conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD). A targeted, unsystematic PubMed search followed by an extensive pearl-growing strategy was applied to further augment study selection based on the extensive expertise of study authors. Overall, most of the evidence currently available suggests a modest benefit for a Zn[2+] supplement of around 25-30 mg/day as an augmentation to MDD treatment, with potential benefits of smaller magnitude in paediatric ADHD. Evidence for perturbations of Zn[2+] as a biomarker of risk for these neuropsychiatric disorders remains unconvincing. The role of Zn[2+] supplements in the treatment of the selected conditions remains largely unknown due to the lack of specific, randomised controlled trials conducted to explore their efficacy. The long-term safety, optimal doses for specific applications, and the exploration of possible biomarkers to stratify patient selection to identify the optimal candidate for Zn[2+] supplements remain unanswered questions.},
}

Humans
*Zinc/metabolism
*Homeostasis
*Mental Disorders/metabolism/etiology
Attention Deficit Disorder with Hyperactivity/metabolism
Animals
Schizophrenia/metabolism
Depressive Disorder, Major/metabolism
Alzheimer Disease/metabolism
Autism Spectrum Disorder/metabolism
Parkinson Disease/metabolism
Bipolar Disorder/metabolism

@article {pmid41303353,
year = {2025},
author = {Rodríguez-Esparragón, F and Cazorla-Rivero, SE and Torrealba, E and Cánovas-Molina, Á and González-Hernández, AN and Martín-Alfaro, R and Afonso-Medina, MP and Martínez de Saavedra-Álvarez, MT and Pérez-Santana, CG and Bartolomé, C and Estupiñán, L and González-Martín, JM and Clavo, B},
title = {Insights into the Biomarker Potential of Humanin and Mots-c Expression and Telomere Length in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210866},
pmid = {41303353},
issn = {1422-0067},
support = {PIFIISC22/15//Fundación Canaria de Investigación Sanitaria/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/blood/metabolism ; Biomarkers/blood ; Male ; Female ; Aged ; Case-Control Studies ; Cognitive Dysfunction/genetics/blood ; *Intracellular Signaling Peptides and Proteins/blood/genetics/metabolism ; Aged, 80 and over ; *Telomere Homeostasis ; *Mitochondrial Proteins/blood/genetics ; RNA, Messenger/genetics ; Middle Aged ; *Telomere/genetics/metabolism ; },
abstract = {Humanin (HN) and MOTS-c are mitochondrial-derived peptides (MDPs) known for their neuroprotective and metabolic functions. Their circulating and tissue levels decline with age and in neurodegenerative diseases such as Alzheimer's disease (AD). This study aimed to evaluate whether blood and plasma gene expression and plasma protein levels of HN and MOTS-c are associated with AD markers, their role in the conversion from mild cognitive impairment (MCI) to AD, and their overall association with the disease. A case-control study was conducted, including patients with AD and MCI, and individuals with subjective cognitive decline (SCD) as controls. Gene expression levels were quantified from total RNA isolated from blood and plasma, normalised to mitochondrial DNA copy number (mtDNA-CN). ELISA was used to measure plasma HN and MOTS-c protein concentrations. HN and MOTS-c transcript levels differed significantly among study groups, whereas plasma protein concentrations did not discriminate between AD and MCI. In silico and RNA decay assays revealed faster degradation of HN mRNA and delayed but stable recovery of MOTS-c mRNA. Overall, blood and plasma transcript levels-but not circulating protein levels-of these MDPs were significantly reduced in AD compared to SCD, suggesting their potential as early biomarkers of Alzheimer's disease.},
}

Humans
*Alzheimer Disease/genetics/blood/metabolism
Biomarkers/blood
Male
Female
Aged
Case-Control Studies
Cognitive Dysfunction/genetics/blood
*Intracellular Signaling Peptides and Proteins/blood/genetics/metabolism
Aged, 80 and over
*Telomere Homeostasis
*Mitochondrial Proteins/blood/genetics
RNA, Messenger/genetics
Middle Aged
*Telomere/genetics/metabolism

@article {pmid41303334,
year = {2025},
author = {Pecoraro, M and Serra, A and Lamberti, MJ and Pascale, M and Franceschelli, S},
title = {New Role of Protein Misfolding Corrector in the ER Stress-Inflammation Axis: Possible Therapeutic Indication in Neuronal and Epithelial Tumor Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210846},
pmid = {41303334},
issn = {1422-0067},
support = {ORSA231580//University of Salerno/ ; },
mesh = {Humans ; *Endoplasmic Reticulum Stress/drug effects ; *Inflammation/metabolism/drug therapy ; *Neurons/metabolism/drug effects/pathology ; Protein Folding/drug effects ; Calcium/metabolism ; Cell Line, Tumor ; Thapsigargin/pharmacology ; A549 Cells ; Epithelial Cells/metabolism/drug effects ; Proteostasis Deficiencies/drug therapy/metabolism ; },
abstract = {Protein misfolding diseases are characterized by structurally abnormal proteins that lose their functionality, resulting in cellular and tissue dysfunction. Neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease, share a common etiopathogenesis characterize by the accumulation of misfolded proteins. These proteins autonomously aggregate within neuronal cells, triggering inflammation and cell death. The accumulation of misfolded proteins triggers endoplasmic reticulum (ER) stress, leading to alter Ca[2+] homeostasis. This prolonged stress condition induces the cleavage of procaspase 4 which is resident in ER and activates NF-kB pathway activation, leading to inflammatory responses and cell death. In this study, the efficacy of the drug Vx-445 (Elexacaftor), used in the pharmacological treatment of cystic fibrosis, was assessed in human adenocarcinomic basal alveolar epithelial (A549) and neuronal (SH-SY5Y) cell lines, where ER stress was induced by Thapsigargin. The aim was to assess whether the corrector was able to reduce ER stress by restoring cellular homeostasis and, probably, the proper folding of misfolded proteins and reducing the inflammatory response triggered by these events. Therefore, protein levels of IkBα, p-STAT 3 and COXII were analyzed by flow cytofluorimetry, while Ca[2+] content was measured by spectrofluorimetry. The results obtained suggest a significant effect of Vx-445 in restoring cellular homeostasis, leading to reduced expression of inflammation-related proteins, such as IL-6, tested by ELISA. Although preliminary, these results encourage further studies to explore the potential repurpose of Vx-445 as a therapeutic candidate for conditions involving ER stress and chronic inflammatory diseases associated with protein misfolding, beyond its current use in cystic fibrosis.},
}

Humans
*Endoplasmic Reticulum Stress/drug effects
*Inflammation/metabolism/drug therapy
*Neurons/metabolism/drug effects/pathology
Protein Folding/drug effects
Calcium/metabolism
Cell Line, Tumor
Thapsigargin/pharmacology
A549 Cells
Epithelial Cells/metabolism/drug effects
Proteostasis Deficiencies/drug therapy/metabolism

@article {pmid41303210,
year = {2025},
author = {Estanga, A and Tellaetxe-Elorriaga, I and Ecay-Torres, M and García Condado, J and García-Sebastián, M and Arriba, M and López, C and Ros, N and Iriondo, A and Reparaz-Escudero, I and Erramuzpe, A and Martínez-Lage, P and Altuna, M},
title = {Cognitive Age Delta as a Marker of Healthy and Pathological Cognitive Aging: The Role of Lifestyle, Cognitive Reserve, and Vascular Risk.},
journal = {Journal of clinical medicine},
volume = {14},
number = {22},
pages = {},
doi = {10.3390/jcm14228176},
pmid = {41303210},
issn = {2077-0383},
support = {PI21/00718//Instituto de Salud Carlos III (Co-funded by European Regional Development Fund; "A way to make Europe")/ ; 2022-CIEN-000088-04-01//Red guipuzcoana de Ciencia, Tecnología e Innovación - Gipuzkoa NEXT 2022 from the Gipuzkoa Provincial Council/ ; },
abstract = {Background: Chronological age is an imprecise proxy for cognitive aging. The Cognitive Age Delta (CAD)-the difference between predicted cognitive age and chronological age-offers a scalable, individualized marker of functional brain aging. We examined determinants of CAD in cognitively unimpaired (CU) adults stratified by Alzheimer's disease (AD) and vascular biomarkers. Methods: We analyzed 177 CU participants from the Gipuzkoa Alzheimer Project (Basque Country, Northern Spain) classified as amyloid-negative/vascular-negative (CUA-V-, n = 140), amyloid-positive (CUA+, n = 23), or vascular-positive (CUV+, n = 14) using CSF and MRI criteria; vascular burden was defined as Fazekas ≥ 2 on T2-FLAIR or ≥4 microbleeds on SWI, excluding non-traumatic superficial siderosis and established ischemic lesions. MRI was used solely for vascular classification. Associations with demographic, genetic, lifestyle, and reserve measures were tested with General Linear Models. Results: CAD did not differ across biomarker groups (Kruskal-Wallis H(2) = 0.17, p = 0.91). Median (IQR) CAD values were 0.28 (-4.13, 4.69) for CUA-V-, -0.14 (-3.15, 2.87) for CUA+, and 0.77 (-2.22, 3.76) for CUV+, indicating comparable distributions. Higher vocabulary scores (proxy of cognitive reserve) related to a younger cognitive age in CUA-V- (β = -1.39, p < 0.001) and CUA+ (β = -2.08, p = 0.054). In CUA+, greater sedentary time-particularly computer-based sitting-was also associated with lower CAD (daily sitting β = -2.13, p = 0.009; workday computer sitting β = -2.32, p = 0.015). CAD showed no associations with CSF Aβ42, p-tau or t-tau, APOE ε4 load, or vascular risk factors (all p > 0.05). Conclusions: CAD captures interindividual resilience-related variability beyond classical AD biomarkers. Vocabulary, a marker of lifelong enrichment, emerged as a robust determinant of a younger cognitive age, while amyloid and vascular pathology exerted limited influence at preclinical stages. These findings support CAD as a sensitive, scalable endpoint for identifying protective factors and guiding personalized prevention in early Aging.},
}

@article {pmid41303105,
year = {2025},
author = {Simfukwe, C and An, SSA and Youn, YC and Kang, J},
title = {Association of qEEG TAR and TBR During Eyes-Open and Eyes-Closed with Plasma Oligomeric Amyloid-β Levels in an Aging Population.},
journal = {Journal of clinical medicine},
volume = {14},
number = {22},
pages = {},
doi = {10.3390/jcm14228069},
pmid = {41303105},
issn = {2077-0383},
support = {2021R1A6A1A03038996//Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education/ ; RS-2024-00507796//Technology Innovation Program grants through Korea Planning & Evaluation Institute of Industrial Technology (KEIT)/ ; },
abstract = {Background/Objective: Timely and successful treatments for Alzheimer's disease (AD) depend on early detection. The Multimer Detection System (MDS-OAβ) for quantifying plasma oligomeric amyloid-β (OAβ) has shown promise as a biomarker of amyloid disease. The theta-to-alpha ratio (TAR) and theta-to-beta ratio (TBR) are two examples of spectral power metrics that can be used in resting-state quantitative EEG (qEEG) to evaluate brain function non-invasively. This study used resting-state EEG (rEEG) recordings obtained while the subjects were both eyes-open (EO) and eyes-closed (EC) to investigate the relationship between regional qEEG power ratios and plasma MDS-OAβ levels in older adults. Methods: The analysis comprised 174 patients between the ages of 60 and 85, with 2 in the low-MDS-OAβ group and 82 in the high-MDS-OAβ group. The clinical plasma cutoff was 0.78 ng/mL. All participants underwent rEEG recordings and plasma OAβ quantification. EEG pre-processing included bandpass filtering (0.5-100 Hz), average re-referencing, artifact rejection using independent component analysis (ICA), and spectral power estimation using Welch's method. The TAR and TBR were calculated across five lobar regions (frontal, central, parietal, occipital, and temporal) during both EO and EC conditions. To normalize data distributions, EEG ratio variables were log-transformed prior to statistical analysis. Group comparisons and linear regression analyses were conducted to evaluate the associations between EEG power ratios and MDS-OAβ levels. Adjusted regression models included age, years of education, and neuropsychological test scores as covariates. Statistical significance was set at p < 0.05. Results: No significant associations were found between TAR and plasma MDS-OAβ levels across any lobar regions under either EO or EC conditions. In contrast, TBR exhibited consistent and significant negative associations with MDS-OAβ levels, particularly under EC conditions. Adjusted regression models revealed that higher MDS-OAβ levels were associated with lower TBR values in the central (β = -0.059, p = 0.015), parietal (β = -0.072, p = 0.006), occipital (β = -0.067, p = 0.040), and temporal (β = -0.053, p = 0.018) lobes, with the strongest inverse relationship observed in the parietal lobe. A similar, though slightly weaker, pattern was observed during EO conditions, with significant inverse associations in the frontal, central, and temporal lobes. Conclusions: Our findings indicate that, after adjusting for covariates, increased plasma MDS-OAβ levels are significantly associated with a reduced TBR, particularly in the parietal and central lobes, under both EO and EC resting-state conditions. In contrast, no significant associations were observed with TAR. These results suggest that a lower TBR may reflect an increased peripheral amyloid burden and highlight its potential as a sensitive qEEG biomarker for early amyloid-related brain changes in older adults.},
}

@article {pmid41302548,
year = {2025},
author = {Abo Mansour, HE and Elberri, AI and Ghoneim, ME and Samman, WA and Alhaddad, AA and Abdallah, MS and El-Berri, EI and Salem, MA and Mosalam, EM},
title = {RETRACTED: Abo Mansour et al. The Potential Neuroprotective Effect of Thymoquinone on Scopolamine-Induced In Vivo Alzheimer's Disease-like Condition: Mechanistic Insights. Molecules 2023, 28, 6566.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {22},
pages = {},
doi = {10.3390/molecules30224436},
pmid = {41302548},
issn = {1420-3049},
abstract = {The journal retracts the article "The Potential Neuroprotective Effect of Thymoquinone on Scopolamine-Induced In Vivo Alzheimer's Disease-like Condition: Mechanistic Insights" [...].},
}

@article {pmid41302511,
year = {2025},
author = {Ward, K and Cole, MH and Griffiths, LR and Sutherland, HG and Winberg, P and Meyer, BJ and Fernandez, F},
title = {Therapeutic Potentials of the Seaweed-Derived Compounds for Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {22},
pages = {},
doi = {10.3390/molecules30224456},
pmid = {41302511},
issn = {1420-3049},
mesh = {*Seaweed/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Animals ; *Neuroprotective Agents/therapeutic use/chemistry/pharmacology ; Antioxidants/therapeutic use/chemistry/pharmacology ; Anti-Inflammatory Agents/therapeutic use/pharmacology/chemistry ; Oxidative Stress/drug effects ; },
abstract = {Cognitive decline associated with healthy ageing and pathological conditions is driven by multifactorial processes, including oxidative stress, mitochondrial dysfunction and chronic neuroinflammation. Alzheimer's Disease (AD), a progressive neurodegenerative disorder affecting cognition and behaviour, is the leading cause of dementia worldwide. Current pharmacological interventions provide modest and transient benefits, targeting limited molecular pathways with safety and cost concerns, underscoring the need for safe, accessible and multi-targeted strategies. This review explores new avenues of therapy with a focus on bioactive compounds derived from brown, red and green seaweeds and their potential to modulate key mechanisms underlying AD. Preclinical and emerging clinical studies demonstrate that phlorotannins, fucoidans, fucoxanthin, lutein, zeaxanthin, ulvan, and astaxanthin exert antioxidant, anti-inflammatory, cholinergic-modulating and neuroprotective effects. Supplementation with seaweed-derived bioactive compounds has been shown to exert molecular and cellular effects that lead to reduced amyloid burden, preservation of synaptic integrity, and enhanced cognitive performance. Collectively, seaweed-derived compounds represent promising candidates for multi-target therapeutic strategies in cognitive decline prevention in the context of AD and healthy brain ageing.},
}

*Seaweed/chemistry
*Alzheimer Disease/drug therapy/metabolism
Humans
Animals
*Neuroprotective Agents/therapeutic use/chemistry/pharmacology
Antioxidants/therapeutic use/chemistry/pharmacology
Anti-Inflammatory Agents/therapeutic use/pharmacology/chemistry
Oxidative Stress/drug effects

@article {pmid41302199,
year = {2025},
author = {Cellot, G and Ballerini, L},
title = {Interplay Among Synaptic Glutamate Release and Excitotoxicity: Neuronal Damage and Graphene-Based Materials Related Protection.},
journal = {Life (Basel, Switzerland)},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/life15111776},
pmid = {41302199},
issn = {2075-1729},
support = {101169352//HORIZON-MSCA-2023-DN-01/ ; NEUR_Ballerini_0915//R_PRIN_2022/ ; NEUR_Ballerini_0837//R_PNRR_PE8_AGE_IT/ ; },
abstract = {Glutamate-related excitotoxicity represents a fundamental pathological process underlying both acute and chronic disorders of the central nervous system. Excessive stimulation of ionotropic and metabotropic glutamate receptors induces ionic dysregulation, mitochondrial dysfunction, and oxidative stress, which can activate necrotic and apoptotic pathways, processes further amplified by defective glutamate clearance and astrocytic impairment. These mechanisms are recognized as key contributors to neuronal damage in ischemic stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease, identifying excitotoxicity as a convergent hallmark of neurodegeneration. Despite considerable progress in elucidating its molecular mechanisms, clinical translation of excitotoxicity-targeted interventions remains limited, largely due to the difficulty of selectively attenuating pathological glutamatergic activity while preserving physiological neurotransmission. Recent advances in nanotechnology, particularly the development of graphene-based materials (GBMs), have offered innovative approaches for neuroprotection. Owing to their unique physicochemical properties and compatibility with neural tissue, GBMs have been investigated as platforms for neural interfacing, regenerative scaffolds, drug delivery platforms, and direct modulators of glutamatergic transmission. In particular, small graphene oxide nanosheets exhibit the capacity to downregulate glutamate release and confer anti-inflammatory and neuroprotective effects. These findings suggest that GBMs may represent a promising class of neuromodulatory tools for mitigating excitotoxic injury, warranting further preclinical and translational investigations.},
}

@article {pmid41302122,
year = {2025},
author = {Kwon, OY and Lee, SH},
title = {Therapeutic Potential of Ishige okamurae Yendo as a Multi-Target Inhibitor Against Dementia Symptoms.},
journal = {Life (Basel, Switzerland)},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/life15111699},
pmid = {41302122},
issn = {2075-1729},
support = {Post-Doctor LAB employment support Program (INU SURE LAB Program) (2024)//Incheon National University/ ; },
abstract = {Ishige okamurae Yendo (I. okamurae) is a brown macroalga with diverse biological activities. Recently, its ameliorative effects against dementia progression have been demonstrated in various in vitro and in vivo models of Alzheimer's disease (AD), glutamate excitotoxicity, and bacterial-driven neuroinflammation. I. okamurae extract (IOE) inhibited AD progression by regulating amyloid beta-induced neuronal death and cognitive impairments. Moreover, IOE attenuated glutamate-induced neurodegeneration by modulating the mitogen-activated protein kinases/Nrf2/heme oxygenase-1 signaling pathway. Furthermore, IOE effectively suppressed lipopolysaccharide-mediated neuroinflammation and memory deficits by downregulating the Toll-like receptor 4/MyD88-dependent signaling pathway. Collectively, these findings highlight the potential of IOE as a natural multi-target, anti-dementia agent. In this review, we summarize the neuroprotective and cognition-enhancing properties of IOE, discuss the molecular mechanisms underlying its action, and consider the advantages of I. okamurae as a promising natural resource for effective therapeutic developments that are capable of targeting multiple pathogenic causes of dementia.},
}

@article {pmid41301903,
year = {2025},
author = {Galanou, ON and Konstandi, M},
title = {Unraveling the Function of PPARα in Neurodegenerative Disorders: A Potential Pathway to Novel Therapies.},
journal = {Biomedicines},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/biomedicines13112813},
pmid = {41301903},
issn = {2227-9059},
abstract = {Alzheimer's (AD) and Parkinson's (PD) diseases are the most prevalent neurodegenerative disorders (NDs), posing a growing global health burden due to the lack of effective therapies. Current treatments offer only limited symptomatic relief without preventing the progression of NDs. In the search for novel therapeutic strategies, peroxisome proliferator-activated receptor alpha (PPARα) has emerged as a promising therapeutic target because mounting evidence suggests that PPARα activation can effectively modify key pathological mechanisms related to NDs, including neuroinflammation, mitochondrial dysfunction, oxidative stress, and impaired transcriptional regulation, processes leading to protein misfolding and aggregation. This review focuses on the potential therapeutic relevance of PPARα activation in AD and PD, discussing mainly insights from preclinical studies. Indicatively, gemfibrozil (PPARα agonist) markedly reduced the beta-amyloid burden, microgliosis, and astrogliosis in the hippocampus of 5xFAD mice and ameliorated their spatial learning and memory. Fenofibrate (PPARα agonist) reduced the depressive-like behavior and memory deficits in rotenone-lesioned rats developing Parkinsonism. It also restricted the depletion of striatal dopamine and protected their substantia nigra pars compacta from dopaminergic neuronal death and α-synuclein aggregation. Clinical trials gave disparate results, indicating either a benefit of fenofibrate in cognitive decline of AD patients or limited efficacy. The role of PPARα agonists in PD is less well established in human trials, which provided limited evidence of neuroprotection and reduced neuroinflammation. Although current findings are promising, they underscore the necessity of further rigorous clinical validation of the efficacy of various PPARα agonists in the retardation or even prevention of AD and PD symptomatology in both genders and the development of reliable biomarkers for the early assessment of the impact of PPARα agonists on NDs. The safety of these drugs in the elderly and their longitudinal effectiveness should also be evaluated.},
}

@article {pmid41301832,
year = {2025},
author = {Christodoulou, RC and Papageorgiou, PS and Sarquis, MD and Rivera, L and Morales Gonzalez, C and Eller, D and Rivera, G and Petrou, V and Vamvouras, G and Vassiliou, E and Papageorgiou, SG and Georgiou, MF},
title = {From Lesion to Decision: AI for ARIA Detection and Predictive Imaging in Alzheimer's Disease.},
journal = {Biomedicines},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/biomedicines13112739},
pmid = {41301832},
issn = {2227-9059},
abstract = {Background: Alzheimer's disease (AD) remains the leading cause of dementia worldwide, with anti-amyloid monoclonal antibodies (MABs) marking a significant advance as the first disease-modifying therapies. Their use, however, is limited by amyloid-related imaging abnormalities (ARIA), which appear as vasogenic edema or effusion (ARIA-E) and hemosiderin-related changes (ARIA-H) on MRI. Variability in imaging protocols, subtle early findings, and the lack of standardized risk models challenge detection and management. Methods: This narrative review summarizes current artificial intelligence (AI) applications for ARIA detection and risk prediction. A comprehensive literature search across PubMed, Embase, and Scopus identified studies focusing on MRI-based AI analysis, lesion quantification, and predictive modeling. Results: The evidence is organized into six thematic domains: ARIA definitions, imaging challenges, foundations of AI in neuroimaging, detection tools, predictive frameworks, and future perspectives. Conclusions: AI offers promising avenues to standardize ARIA evaluation, improve lesion quantification, and enable individualized risk prediction. Progress will depend on multicenter datasets, shared frameworks, and prospective validation. Ultimately, AI-driven neuroimaging may transform how treatment-related complications are monitored in the era of anti-amyloid therapy.},
}

@article {pmid41301782,
year = {2025},
author = {Christodoulou, RC and Vamvouras, G and Papageorgiou, PS and Sarquis, MD and Petrou, V and Rivera, L and Morales, C and Rivera, G and Papageorgiou, SG and Vassiliou, E},
title = {Interpretable Machine Learning for Risk Stratification of Hippocampal Atrophy in Alzheimer's Disease Using CSF Erythrocyte Load and Clinical Data.},
journal = {Biomedicines},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/biomedicines13112689},
pmid = {41301782},
issn = {2227-9059},
abstract = {Background/Objectives: Hippocampal atrophy indicates Alzheimer's disease (AD) progression and guides follow-up and trial enrichment. Identifying high-risk patients is crucial for optimizing care, but accessible, interpretable machine-learning models (ML) are limited. We developed an explainable ML model using clinical data and CSF erythrocyte load (CTRED) to classify adults with AD as high- or low-risk based on hippocampal volume decline. Methods: Included ADNI participants with ≥2 MRIs, baseline lumbar puncture, and vital signs within 6 months of MRI (n = 26). The outcome was the Annual Percentage Change (APC) in hippocampal volume, classified as low or high risk. Predictors were standardized; models included SVM, logistic regression, and Ridge Classifier, tuned and tested on a set (n = 6). Thresholds were based on out-of-fold predictions under a 10-90% positive rate. Explainability used PFI and SHAP for per-patient contributions. Results: All models gave identical classifications, but discrimination varied: Ridge AUC = 1.00, logistic = 0.889, and SVM = 0.667. PFI highlighted MAPres and sex as main signals; CTRED contributed, and age had a minor impact. Conclusions: The explainable ML model with clinical data and CTRED can stratify AD patients by hippocampal atrophy risk, aiding follow-up and vascular assessment planning rather than treatment decisions. Validation in larger cohorts is needed. This is the first ML study to use CSF erythrocyte load to predict hippocampal atrophy risk in AD.},
}

@article {pmid41301726,
year = {2025},
author = {Christodoulou, RC and Vamvouras, G and Sarquis, MD and Petrou, V and Papageorgiou, PS and Rivera, L and Morales, C and Rivera, G and Vassiliou, E and Solomou, EE and Papageorgiou, SG},
title = {Magnetic Resonance Imaging and Cerebrospinal Fluid Biomarker Clustering Defines Biological Subtypes of Alzheimer's Disease.},
journal = {Biomedicines},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/biomedicines13112632},
pmid = {41301726},
issn = {2227-9059},
abstract = {Background/Objectives: Alzheimer's disease (AD) exhibits clinical and biological variability. This study aimed to identify MRI-defined subtypes reflecting distinct biological pathways of neurodegeneration and cognitive decline. Methods: We applied principal component analysis followed by k-means clustering (k = 3) on volumetric MRI data from 924 participants and validated clusters using cerebrospinal fluid (CSF) biomarkers (Aβ42, total tau, p-tau, CTRED, MAPres, glucose, CTWHITE). Results: Three major phenotypes emerged: (1) a tau/vascular limbic subtype with pronounced hippocampal and amygdala atrophy and elevated tau and CTRED levels; (2) a volume-preserved, low-amyloid subtype consistent with early-stage or cognitively resilient AD; and (3) a diffuse-atrophy subtype with high amyloid and tau burden and ventriculomegaly. Comparative analysis revealed progressive biological shifts from amyloid accumulation to tau aggregation and vascular compromise across these clusters. Conclusions: MRI-based clustering validated by CSF biomarkers delineates biologically meaningful AD endophenotypes. The results suggest a gradual cognitive decline driven by amyloid-tau-vascular interactions, supporting multimodal phenotyping as a practical approach for precision staging and intervention.},
}

@article {pmid41301682,
year = {2025},
author = {Bruno, F and Gil, L and Sturiale, V and Guerrero, C and Rebolledo, AB and Brancato, D and Morales, J and Saccone, S and Federico, C},
title = {Loss of AT8 Nuclear Tau as a Marker of Neuronal Ageing and Alzheimer's Disease Progression.},
journal = {Biomedicines},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/biomedicines13112587},
pmid = {41301682},
issn = {2227-9059},
abstract = {Background/Objectives: Tau protein, a central player in Alzheimer's disease (AD) pathology, is classically known for its role in microtubule stabilisation. However, accumulating evidence indicates that tau also localises to the neuronal nucleus, particularly the nucleolus, where it may regulate chromatin organisation and transcription. In this study, we investigated whether different phosphorylation states of nuclear tau display age- and disease-dependent patterns, with a specific focus on the AT8 epitope (phospho-Ser202/Thr205). Methods: We analysed nuclear tau epitopes (Tau-1, AT8, PHF1, T181, and S262) by indirect immunofluorescence in SK-N-BE neuroblastoma cells under proliferative and retinoic acid-induced differentiated conditions and in post-mortem hippocampal CA1 neurons from foetal, young, aged, and AD brains. Other functional markers (UBTF, Ki67, fibrillarin and acetylated histone H4) were used to assess nuclear organisation and function. Results: Compared with the other epitopes, AT8 was unique in showing dynamic nuclear localisation: absent in proliferating cells but present after differentiation, abundant in young neurons, and significantly reduced in aged and AD samples. Nuclear AT8 co-localised with Ki67, and its decline was associated with neuronal cell cycle re-entry and nucleolar disorganisation. Conclusions: Among multiple nuclear tau epitopes, AT8 was the only one displaying age- and disease-related changes, and its reduction during ageing and AD correlates with nuclear stress, aberrant cell cycle activity, and neuronal vulnerability. Loss of nuclear AT8 may therefore represent an early marker of dysfunction in ageing and AD brains.},
}

@article {pmid41301546,
year = {2025},
author = {Hassan, H and Rawlinson, C and Lan, YL and Jenkins, S and Chen, R},
title = {Microglia-Mediated Phagocytosis in Alzheimer's Disease: Mechanisms, Heterogeneity, and Therapeutic Insights.},
journal = {Biomolecules},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/biom15111629},
pmid = {41301546},
issn = {2218-273X},
support = {FS/PhD/22/29304/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {*Alzheimer Disease/pathology/metabolism/therapy/immunology ; Humans ; *Microglia/metabolism/pathology/immunology ; *Phagocytosis ; Animals ; },
abstract = {Microglia are the resident immune cells of the CNS, maintaining brain homeostasis partially through phagocytosis. In Alzheimer's disease (AD), microglial phagocytosis is significantly impaired, contributing to the accumulation of pathological aggregates. Microglial phenotypes are dynamic and can shift depending on the disease stage and local environment. While some subpopulations retain or enhance phagocytic activity, especially under inflammatory conditions, others lose their capacity to clear toxic debris effectively. This variability underscores the need for a more nuanced understanding of microglial regulation and function. This paper explores the dual role of microglial phagocytosis in AD and discusses the emerging insights into microglial heterogeneity and how phenotypic shifts affect phagocytic capacity throughout disease progression. A comprehensive understanding of microglial phagocytosis and its dysregulation in AD is essential for designing targeted treatments. Modulating microglial activity to enhance their protective roles without triggering harmful inflammation represents a promising direction for therapeutic intervention in AD.},
}

*Alzheimer Disease/pathology/metabolism/therapy/immunology
Humans
*Microglia/metabolism/pathology/immunology
*Phagocytosis
Animals

@article {pmid41301520,
year = {2025},
author = {Lope-Piedrafita, S and Serra-Mir, G and Melón, P and Bonaterra, A and Hernández-Guillamon, M and Villegas, S},
title = {ScFv-h3D6 Prevents Bapineuzumab-Induced Hemorrhagic Events in the APP23 Mouse Model of Alzheimer's Disease.},
journal = {Biomolecules},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/biom15111602},
pmid = {41301520},
issn = {2218-273X},
support = {SAF2017-89613R//Ministerio de Economía y Empresa, Spain/ ; PI17-00275//Instituto de Salud Carlos III/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism/genetics/diagnostic imaging ; *Single-Chain Antibodies/pharmacology ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Antibodies, Monoclonal, Humanized/adverse effects ; Humans ; Amyloid beta-Peptides/metabolism ; Cerebral Amyloid Angiopathy/drug therapy ; Magnetic Resonance Imaging ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {The occurrence of amyloid-related imaging abnormalities (ARIAs), found in clinical trials for Aβ-immunotherapy, has been related to the antibody's effector function on glial activation by the Fc portion of the antibody. The use of single-chain variable fragments (scFv) has been proposed as a safer therapeutic strategy. Here, the effects of the mice format of bapineuzumap (mAb-m3D6) and its scFv (scFv-h3D6) on the occurrence of ARIAs in the APP23 mouse model of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) have been addressed by magnetic resonance imaging (MRI). Results are supported by histological and/or biochemical determinations. Aged APP23 mice showed a significantly higher number of microhemorrhages than non-transgenic mice. mAb-m3D6 produced an increase in the number of new hemorrhagic events, mainly in the cortex, whereas scFv-h3D6 did not. Both mAb-m3D6 and scFv-h3D6 reduced Aβ levels by the same extent. Axonal/myelin damage was found in the frontal corpus callosum of APP23 mice, which did not recover after treatment. In conclusion, the scFv-h3D6 format appears safer than the full-length mAb in the APP23 model of AD and CAA. This finding is highly relevant in light of the new FDA- and EMA-approved mAbs, which exclude APOEε4 allele carriers due to the occurrence of hemorrhages.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism/genetics/diagnostic imaging
*Single-Chain Antibodies/pharmacology
Mice
Disease Models, Animal
Mice, Transgenic
*Antibodies, Monoclonal, Humanized/adverse effects
Humans
Amyloid beta-Peptides/metabolism
Cerebral Amyloid Angiopathy/drug therapy
Magnetic Resonance Imaging
Amyloid beta-Protein Precursor/genetics

@article {pmid41301437,
year = {2025},
author = {Prasad, M and Subramanian, ML},
title = {Detecting Alzheimer's Disease Using Ocular Tissue and Imaging: What Do We Know?.},
journal = {Biomolecules},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/biom15111519},
pmid = {41301437},
issn = {2218-273X},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/diagnosis/metabolism/pathology ; Tomography, Optical Coherence/methods ; Biomarkers/metabolism ; *Eye/diagnostic imaging/pathology ; Brain/diagnostic imaging/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition with increasing global prevalence. As early diagnosis becomes critical for timely symptomatic management, noninvasive and easily accessible biomarkers are needed. Given the shared embryologic origins between the eye and the brain, ocular imaging has emerged as a promising diagnostic technique. This review summarizes the associations between AD, ocular imaging and fluid biomarkers in the anterior and posterior segment. We also describe the underlying pathophysiology that explains the connections between each ocular structure and the brain in the context of AD. Optical coherence tomography (OCT), OCT angiography, and fundus photography are the most common imaging modalities utilized in AD research. However, these techniques may or may not be feasible in primary care or neurologic clinical settings. Compared to plasma biomarker analysis, which is minimally invasive and nearing clinical implementation, ocular biomarkers remain primarily valuable in research investigations.},
}

Humans
*Alzheimer Disease/diagnostic imaging/diagnosis/metabolism/pathology
Tomography, Optical Coherence/methods
Biomarkers/metabolism
*Eye/diagnostic imaging/pathology
Brain/diagnostic imaging/metabolism

@article {pmid41301403,
year = {2025},
author = {Zhang, S and Liu, X and Xu, S and Li, W and Song, J and Tian, Q and Du, Y},
title = {Multi-Omics Integration Reveals Electroacupuncture Ameliorates Cognitive Impairment in Alzheimer's Disease via Gut-Brain Axis.},
journal = {Biomolecules},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/biom15111486},
pmid = {41301403},
issn = {2218-273X},
support = {82374564//National Natural Science Foundation of China/ ; 81873380//National Natural Science Foundation of China/ ; 82074566//National Natural Science Foundation of China/ ; 2025AFD596//Hubei Provincial Joint Fund Project/ ; },
mesh = {Animals ; *Electroacupuncture/methods ; *Alzheimer Disease/therapy/metabolism/microbiology ; Mice ; *Gastrointestinal Microbiome ; *Cognitive Dysfunction/therapy/metabolism ; Male ; *Brain/metabolism ; Disease Models, Animal ; Metabolomics ; RNA, Ribosomal, 16S/genetics ; Metabolome ; *Brain-Gut Axis ; Multiomics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) lacks effective therapeutic strategies. Electroacupuncture (EA) offers promising neuroprotective effects, but its underlying mechanisms remain unclear.

OBJECTIVE: To explore the mechanisms of EA's neuroprotective effects on AD via microbiome and metabolome integration.

METHODS: Utilizing a well-established model of AD, Senescence-Accelerated Mouse Prone 8 (SAMP8), EA intervention was performed. 16S ribosomal RNA (rRNA) sequencing and serum metabolomics were conducted on SAMP8 mice, SAMP8 mice after EA intervention, and their normal control group Senescence-Accelerated Mouse Resistant 1 (SAMR1) mice.

RESULTS: SAMP8 mice were subjected to electroacupuncture (EA) treatment at the Baihui (GV20) and Shenshu (BL23) acupoints for 15 min daily over a period of four weeks. EA enhanced cognitive function and reduced neuronal damage in AD models. The treatment lowered pro-inflammatory cytokines (TNF-α, IL-1β) and AD-related pathologies (tau, Aβ1-42). EA also rebalanced gut microbiota by increasing beneficial Gastranaerophilales while decreasing harmful Proteobacteria. Additionally, it restored purine and phenylpropanoid metabolism by regulating key metabolites. Importantly, EA reduced levels of specific metabolites linked to pro-inflammatory bacteria (Sphingomonas, Massilia, Escherichia-Shigella), simultaneously decreasing their abundance. These findings highlight EA's multi-target effects on neuroinflammation, gut microbiota, and metabolic pathways in AD. Notably, the interactions between EA-regulated key metabolites and AD-related targets, predicted via PubChem and ChEMBL databases, remain computational and have not been validated by experimental studies.

CONCLUSIONS: EA exerts neuroprotective effects in AD via modulation of gut microbiota and metabolic pathways, representing a novel non-pharmacological therapeutic strategy.},
}

Animals
*Electroacupuncture/methods
*Alzheimer Disease/therapy/metabolism/microbiology
Mice
*Gastrointestinal Microbiome
*Cognitive Dysfunction/therapy/metabolism
Male
*Brain/metabolism
Disease Models, Animal
Metabolomics
RNA, Ribosomal, 16S/genetics
Metabolome
*Brain-Gut Axis
Multiomics

@article {pmid41301354,
year = {2025},
author = {Gao, J and Liu, L and Yang, Z and Fan, J and For The Alzheimer's Disease Neuroimaging Initiative, },
title = {Predictors of Transition from Mild Cognitive Impairment to Normal Cognition and Dementia.},
journal = {Behavioral sciences (Basel, Switzerland)},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/bs15111552},
pmid = {41301354},
issn = {2076-328X},
support = {2024-BS-160//Natural Science Foundation of Liaoning Province/ ; LJ212410165004//Education Department Project of Liaoning Province/ ; 2024BSL004//Ph.D. Start-up Project of Liaoning Normal University/ ; },
abstract = {Mild cognitive impairment (MCI) represents a heterogeneous state between normal aging and dementia, with varied transition pathways. While factors influencing MCI progression are known, their role in cognitive reversal is unclear. This study analyzed 756 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, classified as progressive MCI (pMCI, N = 272, mean age = 75.10 ± 7.34 years), reversible MCI (rMCI, N = 52, mean age = 69.94 ± 7.98 years) and stable MCI (sMCI, N = 432, mean age = 73.34 ± 7.44 years) based on 36-month follow-up. We compared demographic, lifestyle, clinical, cognitive, neuroimaging, and biomarker data across groups and developed a prediction model. Patients in the rMCI group were significantly younger and had a higher level of education compared with those in the pMCI group. Memory, general cognition, daily functional activities, and hippocampal volume effectively distinguished all three groups. In contrast, Aβ, tau, and other brain regions were able to distinguish only between progressive and non-progressive cases. Informant-reported Everyday Cognition (Ecog) scales outperformed self-reported Ecog scales in differentiating subtypes and predicting progression. Multinomial regression revealed that higher education, larger hippocampal volume, and lower daily functional impairment were associated with reversion, whereas APOE ε4, poorer memory, and greater brain atrophy predicted progression (model accuracy: 78%). The results confirm the significant utility of hippocampal volume, education level, and daily functional activities for assessing baseline disparities and predicting reversion. This study highlights the differential contributions of cognitive abilities and brain regions on MCI reversal, advancing understanding of MCI heterogeneity and providing evidence for precise diagnosis and treatment in early MCI.},
}

@article {pmid41301261,
year = {2025},
author = {McDonough, IM and Bender, AR and Patihis, L and Stinson, EA and Letang, SK and Miller, WS},
title = {Interpreting fMRI Studies in Populations with Cerebrovascular Risk: The Use of a Subject-Specific Hemodynamic Response Function.},
journal = {Behavioral sciences (Basel, Switzerland)},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/bs15111457},
pmid = {41301261},
issn = {2076-328X},
support = {Startup//University of Alabama/ ; P30AG031054//University of Alabama at Birmingham/ ; },
abstract = {Functional magnetic resonance imaging (fMRI) is commonly used to investigate the neural bases of aging and psychological disorders. However, the BOLD signal captured by fMRI is affected by many factors that are non-neural in origin. We tested how vascular health risks, which often go unmeasured in neuroimaging studies, and aging interact to modify the shape and/or timing of the HRF, which then affect the differences in patterns of brain activity in a task-evoked memory encoding paradigm. Adult participants (aged 20-74) answered questions about their health and underwent two fMRI tasks: viewing a flashing checkerboard and a memory encoding task. Aging and vascular risk had the largest impacts on the maximum peak value of the HRF. Using a subject-specific HRF resulted in a dampening of brain activity in task-positive and task-negative regions. Across three vascular risk factors, using a subject-specific HRF resulted in more consistent brain regions that reached significance and larger effect sizes compared with the canonical HRF. These findings serve as a cautious tail when interpreting task-evoked fMRI activity, especially in populations experiencing alterations to brain vasculature including many older adults and people with neurocognitive disorders like Alzheimer's disease and related dementias.},
}

@article {pmid41300833,
year = {2025},
author = {Bai, R and Cheng, Z and Diao, Y},
title = {SLC30A3 as a Zinc Transporter-Related Biomarker and Potential Therapeutic Target in Alzheimer's Disease.},
journal = {Genes},
volume = {16},
number = {11},
pages = {},
doi = {10.3390/genes16111380},
pmid = {41300833},
issn = {2073-4425},
support = {2020NZ010008//the major and Special Projects of Fujian Province/ ; 2022C006R//High level Talent Innovation and Entrepreneurship Project of Quanzhou/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/drug therapy ; *Cation Transport Proteins/genetics/metabolism ; Biomarkers/metabolism ; *Zinc/metabolism ; Transcriptome ; Gene Regulatory Networks ; Gene Expression Profiling ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with unclear pathogenic mechanisms. Dysregulated zinc metabolism contributes to AD pathology. This study aimed to identify zinc metabolism-related hub genes to provide potential biomarkers and therapeutic targets for AD.

METHODS: We performed an integrative analysis of multiple transcriptomic datasets from AD patients and normal controls. Differentially expressed genes and weighted gene co-expression network analysis (WGCNA) were combined to identify hub genes. We then conducted Gene Set Enrichment Analysis (GSEA), immune cell infiltration analysis (CIBERSORT), and receiver operating characteristic (ROC) curve analysis to assess the hub gene's biological function, immune context, and diagnostic performance. Drug-gene interactions were predicted using the DrugBank database.

RESULTS: We identified a single key zinc transporter-related hub gene, SLC30A3, which was significantly downregulated in AD and demonstrated potential diagnostic value (AUC 0.70-0.80). Lower SLC30A3 expression was strongly associated with impaired synaptic plasticity (long-term potentiation, long-term depression, calcium signaling pathway, and axon guidance), mitochondrial dysfunction (the citrate cycle and oxidative phosphorylation), and pathways common to major neurodegenerative diseases (Parkinson's disease, AD, Huntington's disease, and amyotrophic lateral sclerosis). Furthermore, SLC30A3 expression correlated with specific immune infiltrates, particularly the microglia-related chemokine CX3CL1. Zinc chloride and zinc sulfate were identified as potential pharmacological modulators.

CONCLUSIONS: Our study systematically identifies SLC30A3 as a novel biomarker in AD, linking zinc dyshomeostasis to synaptic failure, metabolic impairment, and neuroimmune dysregulation. These findings offer a new basis for developing targeted diagnostic and therapeutic strategies for AD.},
}

Humans
*Alzheimer Disease/genetics/metabolism/drug therapy
*Cation Transport Proteins/genetics/metabolism
Biomarkers/metabolism
*Zinc/metabolism
Transcriptome
Gene Regulatory Networks
Gene Expression Profiling

@article {pmid41300781,
year = {2025},
author = {Yanaizu, M and Takata, Y and Kato, M and Fujiwara, H and Kino, Y},
title = {Transcriptional Activation of the TREM2 Gene by ZEB2 in a Zinc Finger-Dependent Manner.},
journal = {Genes},
volume = {16},
number = {11},
pages = {},
doi = {10.3390/genes16111329},
pmid = {41300781},
issn = {2073-4425},
support = {19K07982//Ministry of Education, Culture, Sports, Science and Technology/ ; 20K07876//Ministry of Education, Culture, Sports, Science and Technology/ ; 21K20700//Ministry of Education, Culture, Sports, Science and Technology/ ; 23K14763//Ministry of Education, Culture, Sports, Science and Technology/ ; },
mesh = {*Receptors, Immunologic/genetics/metabolism ; Humans ; *Membrane Glycoproteins/genetics/metabolism ; Microglia/metabolism ; *Zinc Finger E-box Binding Homeobox 2/genetics/metabolism ; *Transcriptional Activation ; *Zinc Fingers/genetics ; Transcription Factors/genetics/metabolism ; Cell Line ; Promoter Regions, Genetic ; },
abstract = {Background/Objectives: TREM2 is a transmembrane receptor highly expressed in microglia and macrophages, and its involvement in Alzheimer's disease, obesity, and cancer has garnered significant attention. Although its biological function has been actively investigated, the mechanisms by which its expression is regulated remain incompletely characterized. In this study, we aimed to identify transcription factors that modulate TREM2 expression among those reported to be expressed in microglia. Methods: We inserted a 5 kb upstream region of TREM2 into a luciferase reporter vector. This construct was co-expressed with 15 transcription factors, and the TREM2 transcriptional activity was evaluated using luciferase assays. The most promising transcription factor was subsequently knocked down in HMC3 cells, which are derived from human microglia, to assess its effect on endogenous TREM2 expression. Results: Among the 15 transcription factor candidates tested, SPI1 (PU.1), MAFB, CEBPA, ZEB2, and SALL1 most strongly enhanced TREM2 transcriptional activity. ZEB2 was prioritized due to its limited study in microglia and higher co-expression with TREM2. In HMC3 cells, ZEB2 knockdown reduced both TREM2 mRNA and protein levels. Further analysis using domain-deleted mutants of ZEB2 indicated that the zinc finger domains are essential for its transcriptional activity. Analysis using truncated mutants of the TREM2 upstream region suggests that ZEB2 acts on multiple sites within this region. Chromatin immunoprecipitation also suggested an interaction between ZEB2 and the upstream region of TREM2. Conclusions: This study novelly suggests ZEB2 as a transcription factor that promotes TREM2 expression. Further investigation into the role of ZEB2 in various TREM2-associated diseases is warranted.},
}

*Receptors, Immunologic/genetics/metabolism
Humans
*Membrane Glycoproteins/genetics/metabolism
Microglia/metabolism
*Zinc Finger E-box Binding Homeobox 2/genetics/metabolism
*Transcriptional Activation
*Zinc Fingers/genetics
Transcription Factors/genetics/metabolism
Cell Line
Promoter Regions, Genetic

@article {pmid41300737,
year = {2025},
author = {Huang, D and Huang, S and Gao, Y and Yin, L and Pan, L and Xu, W},
title = {Identification of a Four-Gene Signature Based on Metal Metabolism for Alzheimer's Disease Diagnosis.},
journal = {Genes},
volume = {16},
number = {11},
pages = {},
doi = {10.3390/genes16111287},
pmid = {41300737},
issn = {2073-4425},
support = {2022AD10030//the public welfare research project of Jiaxing science and technology bureau/ ; Y202147818//the scientific research fund of the Zhejiang provincial education department/ ; S202513291038//the provincial college students' innovative entrepreneurial training plan program of Jiaxing Nanhu University/ ; },
mesh = {*Alzheimer Disease/genetics/diagnosis/metabolism ; Humans ; *Metals/metabolism ; Biomarkers/metabolism ; Protein Interaction Maps/genetics ; *Transcriptome ; Nomograms ; Glial Fibrillary Acidic Protein/genetics/metabolism ; ROC Curve ; Gene Expression Profiling ; Gene Regulatory Networks ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and dysregulated metal metabolism in the brain is closely linked to its pathogenesis. Methods: In this study, we identified differentially expressed metal metabolism-related genes (DEMGs) associated with AD by integrating data from the GEO dataset GSE132903 and the GeneCards database. Protein-protein interaction (PPI) network analysis was used to identify hub genes, followed by receiver operating characteristic (ROC) curve analysis to assess their diagnostic potential as AD biomarkers. To validate these findings, we performed qRT-PCR experiments on a cellular model and further verified the results using an independent external dataset. Finally, we developed a multigene diagnostic model and constructed a nomogram to predict AD risk. Results: The results demonstrated that six out of the ten hub genes achieved an area under the curve (AUC) greater than 0.75, and four genes (GAD1, GFAP, SYP, and UQCRC2) showed significant potential as candidate biomarkers for AD after further validation. A multigene diagnostic model based on these genes demonstrated strong predictive performance (AUC = 0.861), and a nomogram with high predictive accuracy (C-index = 0.861) was developed to facilitate individualized AD risk assessment. Conclusions: This study identifies four metal metabolism-related genes as promising diagnostic biomarkers for AD and provides a validated multigene model along with a clinically applicable nomogram for individualized risk assessment.},
}

*Alzheimer Disease/genetics/diagnosis/metabolism
Humans
*Metals/metabolism
Biomarkers/metabolism
Protein Interaction Maps/genetics
*Transcriptome
Nomograms
Glial Fibrillary Acidic Protein/genetics/metabolism
ROC Curve
Gene Expression Profiling
Gene Regulatory Networks

@article {pmid41300531,
year = {2025},
author = {Valle, ML and Getaneh, B and William, C and Ghiso, J and Rostagno, A},
title = {Antioxidants Trolox and Methazolamide Protect Microvascular Endothelial Cells from Oxidative Damage Induced by Sporadic and Familial Forms of Oligomeric Amyloid-β.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/antiox14111375},
pmid = {41300531},
issn = {2076-3921},
support = {AG065651//National Institute of Health/ ; },
abstract = {Cerebral amyloid angiopathy (CAA), present in more than 90% of Alzheimer's disease (AD) cases, associates with focal ischemia and neurovascular dysfunction. Genetic variants at positions 21-23 of amyloid beta (Aβ), among them the Dutch mutation (AβE22Q), are primarily linked to CAA and the development of cerebral hemorrhages. An important contributor to CAA pathogenesis is the dysregulation of mitochondria-mediated pathways with concomitant induction of oxidative stress. Using biochemical assays and immunofluorescence microscopy, this work demonstrates the exacerbated formation of reactive oxygen species (ROS) in human brain microvascular endothelial cells after short exposure to soluble oligomers of synthetic homologues of Aβ1-42 and the Dutch variant, inducing lipid peroxidation and protein carbonylation, both markers of oxidative stress. The heterogeneity of the soluble oligomeric assemblies inducing this oxidative response was highlighted by their reactivity with two conformational antibodies recognizing specific and mutually exclusive epitopes associated with either soluble prefibrillar oligomers or soluble fibrillar oligomers. Treatment with the multitarget antioxidants Trolox and methazolamide significantly attenuated the Aβ-mediated ROS production and reduced oxidative stress markers to basal levels. Our data highlight the damaging role of heterogeneous Aβ oligomers and the preventing effect of antioxidants, suggesting ROS modulation as a complementary therapeutic strategy to preserve neurovascular unit integrity.},
}

@article {pmid41300478,
year = {2025},
author = {Fu, Y and Zhang, X and Li, L and Jiang, H and Ren, Q and Yi, T and Zhang, Y and Lu, Y},
title = {PPARα-Mediated Fatty Acid Catabolism in Astrocytes Was Involved in Improvement of Cognitive Dysfunction by Phlorizin in APP/PS1 Mice.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/antiox14111321},
pmid = {41300478},
issn = {2076-3921},
support = {7252230//Yi Lu/ ; },
abstract = {Central lipid metabolism disorders are crucial for the development of Alzheimer's disease (AD). Phlorizin (PHZ) improved lipid metabolism abnormalities in AD nematodes, but its mechanism of action in improving AD-related symptoms and whether it can alleviate AD cognitive impairment remain unclear. To elucidate the effects and mechanisms of PHZ on lipid metabolism disorders in an AD model, gavage administration of PHZ for 8 weeks improved cognitive dysfunction and lipid disorders in APPswe/PSEN1dE9 (APP/PS1) mice. Concurrently, in astrocytes induced by palmitic acid (PA)- mediated lipid metabolic disorder, PHZ treatment improved astrocytic lipid accumulation by upregulating the target peroxisome proliferator-activated receptor α (PPARα) and its downstream pathways, thereby promoting astrocytic fatty acid oxidation. We validated PHZ's strong in vitro binding affinity with PPARα. Co-culture systems of lipid-metabolically disordered astrocytes and neurons further demonstrated that PHZ significantly improved neuronal cell viability and reduced intracellular lipid accumulation, thereby decreasing the expression of enzymes associated with β-amyloid protein (Aβ) production. This study demonstrates that gavage administration of PHZ for 2 months improves cognitive deficits and pathological markers in AD mice. Furthermore, at the cellular level, PHZ may exert its effects by enhancing astrocytic lipid metabolism, thereby preventing neuronal lipotoxicity and mitigating AD progression.},
}

@article {pmid41300346,
year = {2025},
author = {Yeasmin, A and Torrente, MP},
title = {Histone Post-Translational Modifications and DNA Double-Strand Break Repair in Neurodegenerative Diseases: An Epigenetic Perspective.},
journal = {Biology},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/biology14111556},
pmid = {41300346},
issn = {2079-7737},
support = {1R15NS125394-01/NH/NIH HHS/United States ; },
abstract = {DNA damage is a hallmark of the fatal process of neurodegeneration in the central nervous system (CNS). As neurons are terminally differentiated, they accumulate metabolic and oxidative burdens over their whole life span. Unrepaired DNA develops into DNA double-strand breaks (DSBs), which are repaired through homologous recombination (HR) or non-homologous end joining (NHEJ). Being post-mitotic and unable to normally undergo HR, damage and defective repair is especially burdensome to CNS neurons. Current research has not produced treatment to prevent and halt progression of neurodegeneration. Hence, novel targeting strategies are desperately needed. Recent investigations in histone post-translational modifications (PTMs) reveal new mechanistic insight and highlight unexplored targets to ameliorate neurodegeneration. As various histone PTMs dictate and facilitate DSB repair, they represent an underexploited area in investigating DNA damage and incorrect repair aiding neurodegeneration. Here, we review the histone PTM alterations in several neurodegenerative diseases: Amyotrophic Lateral Sclerosis/Frontotemporal Dementia, Parkinson's Disease, Alzheimer's Diseases, Multiple Sclerosis, and Huntington's Disease. These findings emphasize that histone PTM alterations can enable an aberrant DNA damage response (DDR) leading to neurodegeneration. Further research into the connections between histone PTMs and DNA damage in decaying neurons will illuminate novel targets to dampen the aberrant DDR and promote neuronal survival.},
}

@article {pmid41300249,
year = {2025},
author = {Su, R and Li, X and Xie, P and Yuan, Y},
title = {Neurofeedback Training Modulates Brain Functional Networks and Improves Cognition in Amnestic Mild Cognitive Impairment Patients Aged 60-70 Years.},
journal = {Brain sciences},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/brainsci15111243},
pmid = {41300249},
issn = {2076-3425},
support = {QN2024061//Science Research Project of Hebei Education Department/ ; F2019203515//the Key Project of Natural Science Foundation of Hebei Province/ ; F2022203005//the Key Project of Natural Science Foundation of Hebei Province/ ; 236Z2004G//S&T Program of Hebei/ ; UY202201//Medical-Industrial Crossover Special Incubation Project of Yanshan University and The First Hospital of Qinhuangdao/ ; },
abstract = {Background/Objectives: Amnestic mild cognitive impairment (aMCI) represents a transitional stage between normal aging and dementia, constituting a critical intervention window for Alzheimer's disease (AD). As a non-invasive intervention, neurofeedback training (NFT) has demonstrated potential in ameliorating cognitive deficits and clinical symptoms in aMCI patients; however, its mechanistic effects on functional brain connectivity remain inadequately elucidated. Methods: This study employed low- and high-order functional analytical approaches to comprehensively investigate the effects of NFT on dynamic brain functional networks in aMCI. Results: Our findings revealed that following NFT, aMCI patients exhibited enhanced connectivity strength, global efficiency, and nodal characteristics within the delta band, whereas connectivity was generally attenuated in the theta, alpha, and beta bands. Dynamic network analysis indicated increased entropy in short-time windows. Cognitive assessments showed a significant short-term improvement in MoCA scores among 92.9% of participants. Conclusions: These results suggest that NFT effectively remodels brain network activity patterns in aMCI patients, thereby facilitating cognitive improvement. These findings provide preliminary insights into the brain network mechanisms underlying NFT-mediated cognitive enhancement in aMCI.},
}

@article {pmid41300248,
year = {2025},
author = {Min, Y and Lee, YS and Lee, J and Keum, DY and Gwag, JY and Jeon, SM and Jo, H and Kang, SU},
title = {The cGAS-STING Pathway in Dementia: An Emerging Mechanism of Neuroinflammation.},
journal = {Brain sciences},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/brainsci15111241},
pmid = {41300248},
issn = {2076-3425},
support = {NS123456/NS/NINDS NIH HHS/United States ; HI22C2064//Ministry of Health & Welfare, Republic of Korea/ ; },
abstract = {Dementia is a growing global health concern in aging societies, leading to a progressive decline in cognitive function that severely impairs daily life. Despite the growing burden, effective preventive and therapeutic strategies remain elusive, emphasizing the urgent need for novel interventions. Recent advances underscore the pivotal role of neuroinflammation in dementia pathogenesis, particularly in Alzheimer's disease (AD). Chronic activation of central nervous system immune cells, particularly microglia, exacerbates neurodegeneration and establishes a self-perpetuating cycle of inflammation and cognitive decline. This review focuses on emerging research exploring the cGAS-STING pathway's role in dementia, examining its potential as a diagnostic and therapeutic target. The cGAS-STING pathway, integral to innate immune responses, may contribute to the chronic neuroinflammation seen in neurodegenerative diseases. By targeting this pathway, new strategies could mitigate the inflammatory processes that drive neuronal loss, offering a promising avenue for therapeutic development in dementia.},
}

@article {pmid41300247,
year = {2025},
author = {Gumenyuk, V and Korzyukov, O and Parker, SM and Murman, DL and Miller, NR and Rizzo, M},
title = {ERP Biomarkers of Auditory-Visual Distraction in Aging and Cognitive Impairment.},
journal = {Brain sciences},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/brainsci15111242},
pmid = {41300247},
issn = {2076-3425},
abstract = {Background/Objectives: Distraction is a form of impaired selective attention that becomes more pronounced with normal aging and in pathological conditions such as mild cognitive impairment (MCI) and Alzheimer's disease (AD). Event-related potentials (ERPs) provide sensitive, time-resolved measures of neural mechanisms underlying distractibility. This study aimed to identify age- and disease-related ERP signatures of auditory-visual distraction as potential functional biomarkers for cognitive decline. Methods: Forty-six participants were enrolled, including young controls (Y), healthy older controls (O), individuals with MCI, and individuals with AD. Participants performed cross-modal interference tasks in which irrelevant auditory distracting sounds were paired with a relevant visual discriminating task. The distraction potential was quantified as the difference between ERP responses to novel distractors and standard stimuli, focusing on three core components: N1-enhancement, P3a, and reorienting negativity (RON). Behavioral measures (accuracy, reaction time, miss responses) were also assessed. Results: Compared to Y, O showed increased N1-enhancement and reduced P3a and RON amplitudes, consistent with age-related susceptibility to distraction. Patients with MCI and AD exhibited further abnormalities, including diminished P3a and altered RON responses, suggesting impaired orientation and reorientation of attention. Behavioral distraction effect was observed in all groups, with no significant difference between groups. ERP-cognition correlations indicated that reduced P3a amplitude and delayed RON were associated with executive dysfunction and memory deficits. Conclusions: ERP signatures of distraction, particularly altered P3a and RON components, differentiate normal aging from pathological decline and may serve as functional biomarkers for early detection of MCI and AD. These findings highlight the translational potential of distraction paradigms in clinical assessment of aging-related cognitive impairment.},
}

@article {pmid41300242,
year = {2025},
author = {Kuzubova, E and Radchenko, A and Pokrovskii, M and Shcheblykina, O and Chaprov, K and Nesterov, A and Avtina, T and Pokrovskii, V and Korokin, M},
title = {Sex-Dependent Phenotypic and Histomorphometric Biomarkers in the APPswe/PS1dE9/Blg Mouse Model of Alzheimer's Disease.},
journal = {Brain sciences},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/brainsci15111237},
pmid = {41300242},
issn = {2076-3425},
support = {075-15-2025-558//Ministry of Science and Higher Education of the Russian Federation/ ; },
abstract = {Background: Sex-related differences significantly impact biomedical research outcomes, yet female subjects are often excluded due to concerns about variability from the estrous cycle. This study aimed to investigate the sex-dependent differences in behavioral phenotypes and amyloid-beta plaque accumulation in the APPswe/PS1dE9/Blg transgenic mouse model of Alzheimer's disease. Methods: Male and female APPswe/PS1dE9/Blg transgenic mice and wild-type (WT) controls were assessed at 7.5 and 10 months of age. A comprehensive behavioral test battery was employed, including the Open Field, Novel Object Recognition, Y-Maze, and Barnes Maze tests. Histological analysis of amyloid plaque was carried out. Results: Female transgenic mice displayed delayed accumulation of Aβ plaques and milder cognitive decline compared with males. At 10 months, plaque load in females corresponded to that of 7.5-month-old males, demonstrating a temporal lag in pathology. Behavioral impairments correlated negatively with cortical plaque burden (r = -0.4964, p = 0.0181), supporting its role as a structural biomarker of disease progression. Conclusions: This study identifies distinct sex-dependent trajectories of behavioral and histomorphometric biomarkers in APPswe/PS1dE9/Blg mice. Females exhibit delayed amyloid pathology and cognitive decline, suggesting intrinsic neuroprotective mechanisms that modulate biomarker expression over time. These findings emphasize the necessity of integrating both sexes in preclinical biomarker research and support the use of morphometric endpoints as translationally relevant indicators of Alzheimer's disease progression.},
}

@article {pmid41300237,
year = {2025},
author = {Joo, J and Yang, WS and Koh, HJ},
title = {Hippocampal Development and Epilepsy: Insights from Organoid Models.},
journal = {Brain sciences},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/brainsci15111231},
pmid = {41300237},
issn = {2076-3425},
support = {RS-2023-00278088//the National Research Foundation of Korea/ ; },
abstract = {The hippocampus is a crucial component of the human brain. It is located on the medial side of the temporal lobe and is connected to the limbic system, influencing memory and cognitive function. The critical functions of the hippocampus have a profound impact on an individual's overall ability to maintain daily life functioning. In adults, hippocampal damage impairs cognitive functions, including memory, learning, and emotional regulation. It is associated with conditions such as memory impairment, Alzheimer's disease, various forms of dementia, depression, and stress-related disorders. Damage to the developing hippocampus can have broad and profound, leading to deficits in memory development, language acquisition, and behavioral and emotional regulation, thereby impairing the individual's ability to maintain normal daily functioning. One of the major factors affecting hippocampal development is epilepsy. Therefore, identifying the mechanism underlying epilepsy-induced hippocampal damage and developing therapeutic strategies to reduce or prevent epileptic events that significantly impair hippocampal maturation are of critical importance. Numerous studies have been conducted in this regard, and given the challenges of directly studying the human brain, organoid-based research approaches have gained increasing attention and widespread application. In particular, hippocampal organoids have emerged as valuable models for investigating various hippocampal functions; however, definitive findings have yet to be established. Therefore, elucidating the structural characteristics and underlying mechanisms of epilepsy using hippocampal organoids, and exploring potential strategies to mitigate its effects remains an important direction for future research.},
}

@article {pmid41300212,
year = {2025},
author = {Shaw, J and Rodgers, F and Kavustu, DE and Wang, Y and Assaad, S and Livingston, G and Sommerlad, A},
title = {Factors Associated with the Social Behaviour of People with Alzheimer's Dementia: A Video Observation Study.},
journal = {Brain sciences},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/brainsci15111205},
pmid = {41300212},
issn = {2076-3425},
support = {222932/Z/21/Z/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Background/Objectives: People with Alzheimer's dementia (AD) experience distressing changes in social behaviour. However, little is understood about whether social behaviour is associated with support provided by, or familiarity with, conversation partners. We aimed to explore the association between support provided by, and familiarity with, conversation partners and the social behaviour of people with mild AD during conversation. Method: We designed an exploratory within-subjects study wherein conversations between 19 participants with mild AD and a familiar informant, followed by an unfamiliar researcher, were video-recorded and double-rated using two measures of social behaviour (Social Observation Inventory and Measure of Participation in Conversation-Dementia), and one measure of support from the conversation partner (Measure of Support in Conversation-Dementia). Multilevel linear regression with within-subject clusters was used to explore adjusted associations between support and familiarity and social behaviour. Results: Greater support in conversation was associated with more appropriate participation in social conversation of participants with AD. In fully adjusted models, every 1-point increase in MSC-D score was associated with a 0.29 (95% CI: 0.14 to 0.44) increase in MPC-D score and a 1.59 (95% CI: 0.87 to 2.32) increase in SOI score. Familiarity with the conversation partner was not associated with the social behaviour of the participants with AD. Conclusions: We found evidence for an association between social behaviour in AD and support provided by unimpaired conversation partners, but the numbers were small, and this should be interpreted cautiously. Future research should continue this hypothetical lead to expand our understanding of how support and familiarity influence social behaviour to inform potential interventions.},
}

@article {pmid41300191,
year = {2025},
author = {Kishimoto, Y and Kubota, T and Nakashima, K and Kirino, Y},
title = {rTg4510 Tauopathy Mice Exhibit Non-Spatial Memory Deficits Prevented by Doxycycline Treatment.},
journal = {Brain sciences},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/brainsci15111183},
pmid = {41300191},
issn = {2076-3425},
support = {20790084//Japan Society for the Promotion of Science/ ; 24590133//Japan Society for the Promotion of Science/ ; 16K08215//Japan Society for the Promotion of Science/ ; },
abstract = {Background: Hyperphosphorylated tau accumulation and neurofibrillary tangles (NFTs) are hallmarks of tauopathies, including Alzheimer's disease (AD), and are strongly associated with cognitive decline. The rTg4510 mouse model, which expresses mutant human tau (P301L), develops progressive tauopathy in the absence of amyloid-β pathology, providing a valuable tool for investigating tau-driven neurodegeneration. Previous studies have demonstrated spatial and object-recognition memory deficits at six months of age, which can be prevented by doxycycline (DOX)-mediated suppression of tau expression. However, it remained unclear whether non-spatial hippocampal learning, particularly temporal associative learning, would be similarly affected. Methods: We evaluated six-month-old rTg4510 mice with or without DOX treatment. To control for potential motor confounds, we first assessed spontaneous home cage activity. We then tested hippocampus-dependent non-spatial learning using two paradigms: trace eyeblink conditioning (500-ms trace interval) and contextual fear conditioning. Results: General motor function remained intact; however, rTg4510 mice without DOX treatment exhibited increased rearing behavior. These mice demonstrated significant deficits in trace eyeblink conditioning acquisition, with particularly clear impairment on the final day of training. Contextual fear conditioning showed milder deficits. Analysis of response peak latency revealed subtle temporal processing abnormalities during early learning. Two months of DOX treatment initiated at four months of age prevented these learning deficits, confirming their association with tau overexpression. Conclusions: Our findings demonstrate that rTg4510 mice exhibit deficits in non-spatial temporal associative learning alongside previously reported spatial and object-recognition impairments. Trace eyeblink conditioning serves as a sensitive behavioral assay for detecting tau-related hippocampal dysfunction, and the prevention of learning deficits by DOX treatment highlights its potential utility as a translational biomarker for evaluating tau-targeted interventions.},
}

@article {pmid41300189,
year = {2025},
author = {Nikolin, S and Wang, M and Moffa, A and Huang, H and Xu, M and Pande, SR and Martin, D},
title = {An Investigation of the Modulating Effects of Sensory Stimulation and Transcranial Magnetic Stimulation on Memory-Related Brain Activity.},
journal = {Brain sciences},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/brainsci15111182},
pmid = {41300189},
issn = {2076-3425},
abstract = {Background/Objectives: As the global population ages, the prevalence of disorders associated with memory dysfunction (e.g., Alzheimer's disease) continues to increase. There is a need for novel interventions that can enhance memory and support affected individuals. Non-invasive brain stimulation provides a promising approach to engage circuits within the hippocampal network, a group of brain regions critical for episodic memory, and thereby improve cognition. Methods: Twenty healthy participants completed a single-blind, within-subject crossover study over four sessions. In each session, they received one of four interventions whilst viewing pictures of real-world objects: 40 Hz synchronised audiovisual stimulation (AVS), theta burst stimulation (TBS), a combination of synchronised 5 Hz repetitive transcranial magnetic stimulation with AVS (rTMS + AVS), or sham rTMS. Electroencephalography (EEG) was recorded to measure associated brain activity changes. Following each intervention, participants completed a recognition memory task. Results: Mixed-effect repeated measure models (MRMMs) revealed no significant differences in recognition memory performance or theta (5 Hz) activity across conditions. However, both TBS and rTMS + AVS significantly increased gamma (40 Hz) activity compared to sham rTMS, and TBS induced a widespread increase in theta-gamma phase-amplitude coupling during picture viewing. Conclusions: While the neuromodulatory interventions did not enhance memory performance, the observed increase in gamma activity, particularly following rTMS-based stimulation, suggests potential engagement of neural processes associated with memory. These findings warrant further investigation into the role of gamma oscillations in memory and cognitive enhancement.},
}

@article {pmid41300171,
year = {2025},
author = {Costa, ACS and Brandão, AC and Leiva, V and Taylor, HG and Johnson, MW and Salmona, P and Abreu-Silveira, G and Scheidemantel, T and Roizen, NJ and Ruedrich, S and Boada, R},
title = {Baseline Neuropsychological Characteristics of Adolescents and Young Adults with Down Syndrome Who Participated in Two Clinical Trials of the Drug Memantine.},
journal = {Brain sciences},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/brainsci15111164},
pmid = {41300171},
issn = {2076-3425},
support = {R03AG086928/AG/NIA NIH HHS/United States ; 100.10500.100.0001C//University Hospitals Cleveland's Center for Neurodegenerative Disorders/ ; 3U24AG057437//University Hospitals Cleveland's Center/ ; },
abstract = {BACKGROUND/OBJECTIVES: Down syndrome (DS) is a neurodevelopmental and neurodegenerative disorder typically caused by trisomy 21. We recently concluded a two-site (Ohio, USA and São Paulo, Brazil), phase-2, randomized trial to evaluate the efficacy, tolerability, and safety of the drug memantine in enhancing cognitive abilities of adolescents and young adults with DS. This trial was a follow-up study to a pilot trial performed in Colorado, USA. Results of these two clinical trials have been published elsewhere. Here, we present a comparative analysis of the baseline neuropsychological assessments at the three sites of these two studies, including their psychometric properties, and an account of the considerations involved in the test battery design. We compared test results in the different sites as a way of evaluating the replicability and generalizability of the test results. The distribution of the test results at each site was analyzed and combined when no differences were detected between the mean values of these results. We used post-treatment data from the placebo arms of these studies to quantify test-retest reliability.

RESULTS: Most measures had comparable mean values across test sites, and had good-to-excellent feasibility, few floor effects, and good-to-excellent test-retest reliability. A few measures, however, were deemed unsuitable for use in future studies.

CONCLUSIONS: This study demonstrated remarkable consistency of results across studies in two countries with significantly different cultures and levels of socioeconomic development, which provides supporting evidence for the future design and implementation of similar multicenter, international clinical studies involving participants with DS.},
}

@article {pmid41300161,
year = {2025},
author = {Watson, N and Quimby, M and Hochberg, D and Dickerson, BC and Putcha, D},
title = {The Heterogeneity of Reading and Spelling Deficits in Posterior Cortical Atrophy.},
journal = {Brain sciences},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/brainsci15111154},
pmid = {41300161},
issn = {2076-3425},
support = {K23 AG065450/NH/NIH HHS/United States ; R01 DC014296/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Posterior Cortical Atrophy (PCA) is a clinical syndrome marked by progressive visuospatial impairment, usually due to underlying Alzheimer's disease. While reading and spelling deficits are recognized clinical features of this syndrome, the contributions of visuoperceptual versus linguistic deficits to these impairments are still unclear.

METHODS: To that end, we examined reading and spelling performance in 23 individuals from the Massachusetts General Hospital PCA cohort. Participants completed tests of reading from the Western Aphasia Battery and spelling to dictation from the Boston Diagnostic Aphasia Examination. A mixed-methods analysis included quantitative scoring and qualitative observations of visual behaviors, error patterns, and compensatory strategies.

RESULTS: Participants commonly demonstrated visual scanning errors, difficulty following multi-line text, and spelling errors reflecting both visual-perceptual and orthographic-linguistic breakdowns.

CONCLUSIONS: Because reading and spelling in PCA are variably impaired cognitive skills driven by visual deficits and lexical vulnerability, assessments and interventions must account for deficits in both cognitive processes. Our findings highlight the vulnerability of reading and spelling in PCA and underscore the need for multimodal assessment strategies that account for the interplay of visual, phonological, and lexical processes. These insights can inform diagnosis and guide the development of accessible interventions tailored to optimize compensatory strategies to support functional language abilities.},
}

@article {pmid41299782,
year = {2025},
author = {Chen, Z and Mao, Z and Tang, W and Shi, Y and Liu, J and You, Y},
title = {Immunosenescence in aging and neurodegenerative diseases: evidence, key hallmarks, and therapeutic implications.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {60},
pmid = {41299782},
issn = {2047-9158},
support = {81873778//National Natural Science Foundation of China/ ; 82071415//National Natural Science Foundation of China/ ; 82060213//National Natural Science Foundation of China/ ; NRCTM(SH)-2021-03//National Research Center for Translational Medicine at Shanghai, Ruijin/ ; 825MS173//Hainan Provincial Natural Science Foundation of China/ ; Hnky2025-21//Scientific Research Project of Hainan Higher Education Institutions/ ; },
mesh = {Humans ; *Immunosenescence/physiology/immunology ; *Aging/immunology ; *Neurodegenerative Diseases/immunology/therapy ; Animals ; Cellular Senescence/immunology ; },
abstract = {Aging is a multifaceted biological process affecting various organ systems. Immunosenescence, a key feature of aging, markedly increases susceptibility to infections, cancers, autoimmune diseases, and also neurodegenerative disorders. Immunosenescence not only accelerates normal aging but also drives the progression of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). However, the lack of a consensus on the mechanistic hallmarks of immunosenescence presents a major barrier to the development and validation of anti-aging therapies. In this review, we propose 11 hallmarks of immunosenescence: genomic instability, telomere attrition, epigenetic dysregulation, stem cell exhaustion, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, chronic inflammation, altered intercellular communication, and microbiome dysbiosis. We also elucidate the intricate interplay between immunosenescence and both normal brain aging and neurodegenerative pathologies, highlighting the pivotal involvement of age-related immune dysregulation in the pathogenesis of neurodegenerative disorders. This mechanistic connection is particularly evident in prototypical neurodegenerative conditions such as AD and PD, where immunosenescence appears to significantly contribute to disease progression and phenotypic manifestations. Given that the ultimate goal of immune aging research is to prevent or alleviate age-related diseases, we also discuss potential hallmark-targeting anti-immunosenescence strategies to delay or even reverse normal aging and neurodegeneration.},
}

Humans
*Immunosenescence/physiology/immunology
*Aging/immunology
*Neurodegenerative Diseases/immunology/therapy
Animals
Cellular Senescence/immunology

@article {pmid41299754,
year = {2025},
author = {Xu, C and Liu, G and Ji, H and Yao, Q and Cui, W and Xu, S and Zhou, X and Yu, J and Wang, Q},
title = {Association of DRD4 promoter-associated methylation with mild cognitive impairment in Han and Uygur populations.},
journal = {European journal of medical research},
volume = {30},
number = {1},
pages = {1185},
pmid = {41299754},
issn = {2047-783X},
support = {2024C03101//Zhejiang Key Research and Development Project/ ; 32171035//National Natural Science Foundation of China/ ; U1503223//National Natural Science Foundation of China/ ; 2023Z173//Ningbo Key Research and Development Project/ ; },
mesh = {Humans ; *Cognitive Dysfunction/genetics ; Male ; Female ; *DNA Methylation ; *Receptors, Dopamine D4/genetics ; Aged ; *Promoter Regions, Genetic ; China ; Middle Aged ; Case-Control Studies ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease characterized by subjective cognitive decline and objective evidence of cognitive impairment revealed through neuropsychological examinations. Dopamine receptors play a pivotal role in the modulation of memory and cognitive functions. DRD4 is a dopamine receptor gene enriched in memory-related brain regions, modulates synaptic plasticity, and its promoter methylation status. While DRD4 promoter methylation is implicated in neurodevelopmental disorders, its role in MCI pathogenesis remains uninvestigated across ethnically diverse populations.

PURPOSE: Our study focused on the association between DRD4 methylation and MCI in Uygur and Han populations.

PATIENTS AND METHODS: 192 age-sex-matched participants (48 Uygur MCI, 48 Uygur controls, 48 Han MCI, 48 Han controls) were recruited from Xinjiang and Zhejiang, China. MCI diagnosis followed DSM-IV criteria with cognitive assessment (MMSE/MoCA). Peripheral blood DNA underwent bisulfite conversion, followed by pyrosequencing of DRD4 promoter CpG sites 1-4 (PyroMark Q24). Group comparisons used independent t-tests with two-way ANOVA for covariate adjustment (age/sex/ethnicity); Pearson/Spearman tests assessed methylation-biomarker correlations. Methylation was measured using bisulfite pyrosequencing.

RESULTS: Our results indicated that MCI-related hypermethylation was detected in the Uygur (CpG1) and Han (CpG1-3) populations, and subgroup analyses by sex in the Uygur population displayed consistent results, while in the Han subgroup, DRD4 hypermethylation was only observed in the male group. Ethnic differences in CpG4 (CpG: cytosine phosphate guanine) in male cases, CpG1 in overall control, and CpG3 in male controls. Regional distinctions were shown between CpG1and CpG4 in the male subgroup. Diverse correlations were observed. CpG1 methylation in the Uygur male control groups, Uygur female case groups, and Han female control groups was significantly correlated with age, Glu, and HDL-C, respectively. CpG2 in Uygur male controls and Uygur female patients showed correlations with Glu and TG levels. CpG3 in Uygur male and Han male controls was significantly correlated with TC and HDL-C levels. CpG4 in Uygur female controls and Han female patients correlated with Glu and age.

CONCLUSION: Our findings provide novel insights into DRD4 methylation in Uygur and Han populations.},
}

Humans
*Cognitive Dysfunction/genetics
Male
Female
*DNA Methylation
*Receptors, Dopamine D4/genetics
Aged
*Promoter Regions, Genetic
China
Middle Aged
Case-Control Studies

@article {pmid41299730,
year = {2025},
author = {Seong, WJ and An, SJ and Gim, J and Gupta, DP and Park, J and Kang, S and Lee, KH and Song, GJ},
title = {Adenylate kinase 5, a novel genetic risk factor for Alzheimer's disease, regulates microglial inflammatory activation.},
journal = {Molecular brain},
volume = {18},
number = {1},
pages = {89},
pmid = {41299730},
issn = {1756-6606},
support = {NRF-2022R1A4A1018963//National Research Foundation of Korea/ ; HU23C0199//Korea Dementia Research Center/ ; },
mesh = {*Alzheimer Disease/genetics/enzymology/pathology ; *Microglia/pathology/enzymology/metabolism/drug effects ; Animals ; Humans ; *Adenylate Kinase/genetics/metabolism ; Polymorphism, Single Nucleotide/genetics ; *Inflammation/pathology/genetics/enzymology ; *Genetic Predisposition to Disease ; Risk Factors ; Mice, Inbred C57BL ; Male ; Lipopolysaccharides ; Mice ; Female ; Genome-Wide Association Study ; Phagocytosis/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and neuroinflammation, primarily mediated by microglia. In this study, we investigate the role of adenylate kinase 5 (AK5) in microglial function and its association with AD-related pathology. Analysis of brain tissues from AD patients and AD model mice revealed a significant reduction in AK5 expression. In vitro knockdown of AK5 in microglial cells attenuated lipopolysaccharide-induced pro-inflammatory responses, including decreased nitric oxide and tumor necrosis factor-alpha production, while enhancing phagocytic activity. Moreover, AK5 silencing induced metabolic reprogramming, evidenced by reduced lipid droplet accumulation and adipose triglyceride lipase mRNA levels, alongside increased farnesoid X receptor mRNA expression. Genome-wide association studies further identified two AK5 single nucleotide polymorphisms (SNPs), rs59556669 and rs75224576, significantly associated with hippocampal and amygdala atrophy as well as increased AD risk. Notably, these SNPs were not in linkage disequilibrium with the apolipoprotein E (APOE) locus, suggesting that AK5 may represent an independent genetic risk factor for AD. Collectively, our findings identify AK5 as a key regulator of microglial immune and metabolic function. The presence of AK5 variants may contribute to AD susceptibility, and AK5 expression or genetic status could serve as a potential biomarker for early risk assessment. Further exploration of AK5-targeted interventions may provide new therapeutic avenues for AD prevention or treatment.},
}

*Alzheimer Disease/genetics/enzymology/pathology
*Microglia/pathology/enzymology/metabolism/drug effects
Animals
Humans
*Adenylate Kinase/genetics/metabolism
Polymorphism, Single Nucleotide/genetics
*Inflammation/pathology/genetics/enzymology
*Genetic Predisposition to Disease
Risk Factors
Mice, Inbred C57BL
Male
Lipopolysaccharides
Mice
Female
Genome-Wide Association Study
Phagocytosis/drug effects

@article {pmid41299728,
year = {2025},
author = {Vaziri, Y and Olia, JBH and Avci, CB and Nourazarian, A},
title = {Molecular mechanisms of gut microbiota dysbiosis and metabolites in Alzheimer's disease pathogenesis: implications for precision therapeutics.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-025-01263-1},
pmid = {41299728},
issn = {1756-6606},
abstract = {Alzheimer's disease (AD) originates from both central and peripheral pathways. The gut microbiota is a clear risk factor. In AD, microbiota imbalances drive immune system activation, disrupt protective barriers, and alter neuromodulatory signaling. Additionally, gut microbiota dysbiosis has been identified as a risk factor for AD. Recent research indicates that dysbiosis of the microbiota in AD is linked to immune activation, barrier dysfunction, and neuromodulatory signaling. Studies of AD pathology reveal that short-chain fatty acids, indole derivatives, and bile acids can have both protective and harmful effects. New strategies, such as probiotics, dietary changes, and fecal microbiota transplantation, may influence disease progression in AD. However, conflicting methods, unaccountable motives, and ethical concerns surrounding microbiome interventions pose significant hurdles. To translate findings related to the gut-brain axis into effective solutions, we need standardized multi-omics approaches, personalized therapies, and oversight from regulatory authorities. Ultimately, leveraging insights from the gut microbiome holds great promise for transforming how we diagnose, prevent, and treat AD.},
}

@article {pmid41299626,
year = {2025},
author = {Lozzi, F and Camera, E and Cardinali, G and Di Nardo, A},
title = {Exploring the skin as an open window onto neurodegenerative diseases.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {61},
pmid = {41299626},
issn = {2047-9158},
support = {RC-2025//Ministero della Salute/ ; RF-202112374216//Ministero della Salute/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/diagnosis ; *Skin/metabolism/pathology ; Biomarkers/metabolism ; Animals ; },
abstract = {Neurodegenerative diseases (NDDs), including Parkinson's disease and Alzheimer's disease, are major age-related disorders characterized by progressive neuronal degeneration and a decline in cognitive and motor functions. Managing NDDs poses an increasing healthcare challenge as the global population ages. The onset of NDDs is linked to protein misfolding, oxidative stress, dysfunction of mitochondria and lysosomes, and neuroinflammation. Clinical manifestations of NDDs only appear after substantial neuronal damage has already occurred. This underscores the urgent need for accessible tissue biomarkers to enable early diagnosis, disease monitoring and assessment of therapeutic efficacy. The skin has emerged as a valuable peripheral indicator of neurodegeneration, sharing embryological origin, gene expression profiles, protein alterations and cellular dysfunctions with the brain. Notably, pathological protein deposits, which are hallmarks of NDDs, such as beta-amyloid, tau proteins, and oligomeric alpha-synuclein, have been observed in the skin. Increasing evidence links NDDs with various pathological skin conditions, including melanoma and inflammatory diseases. This review aims to explore the potential of the skin as a window into neurodegenerative processes at an early stage, before clinical signs arise. The main advantages of using skin as a source of NDD biomarkers are its accessibility and the minimally invasive sampling methods such as stratum corneum collection, sebum and volatile compounds analysis, and biopsies. Immunohistochemistry and omics approaches applied to skin samples provide valuable insights into NDD pathophysiology and facilitate biomarker discovery for early diagnosis and disease monitoring. NDDs are multisystemic disorders and new findings in skin research highlight the value of peripheral tissues for investigating central nervous system alterations enabling earlier neuroprotective interventions.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology/diagnosis
*Skin/metabolism/pathology
Biomarkers/metabolism
Animals

@article {pmid41299592,
year = {2025},
author = {Zoltowska, KM and Bandera, J and Hamed, MB and Enzlein, T and Hopf, C and Ryan, NS and Chávez-Gutiérrez, L},
title = {The relationship between amyloid-β peptide spectrum and the spastic paraparesis phenotype in autosomal dominant Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {252},
pmid = {41299592},
issn = {1758-9193},
support = {20220007//Stichting Alzheimer Onderzoek (SAO)/ ; INST874/9-1//Deutsche Forschungsgemeinschaft/ ; G008023N//Fonds Wetenschappelijk Onderzoek/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/complications/metabolism ; Presenilin-1/genetics ; *Paraparesis, Spastic/genetics/metabolism ; *Amyloid beta-Peptides/metabolism/genetics ; Phenotype ; Mutation/genetics ; Male ; Female ; *Peptide Fragments/metabolism ; },
abstract = {BACKGROUND: More than 300 mutations in presenilin 1 (PSEN1) lead to autosomal dominant Alzheimer's disease (ADAD). PSEN1, as the catalytic subunit of γ-secretase, generates amyloid-β (Aβ) peptides through a sequential proteolysis of the amyloid precursor protein (APP). While ADAD typically presents with progressive cognitive decline, ~ 25% of PSEN1 mutation carriers develop spastic paraparesis (SP), a debilitating motor condition. The molecular basis of this phenotypic heterogeneity remains unknown. This study examines Aβ profiles generated by PSEN1 variants associated with different clinical presentations with the aim of exploring potential associations between different Aβ profiles and clinical heterogeneity.

METHODS: We analysed reported Aβ peptide profiles generated in vitro by 160 PSEN1 variants, categorized by their associated AD or AD + SP phenotype. We employed an integrated analytical approach combining univariate comparisons of Aβ profiles with machine learning classification.

RESULTS: AD + SP-linked mutations showed significantly higher Aβ43 levels and more severe impairments in γ-secretase processivity compared to pure dementia associated variants. Machine learning consistently identified Aβ43 as the most important feature allowing for the phenotypic classification. Unlike processivity impairments, total Aβ production was comparable between groups, suggesting specific rather than global alterations in γ-secretase function.

CONCLUSIONS: Our analysis reveals a robust association between elevated Aβ43 levels and SP development in PSEN1 mutation carriers. While this correlation does not establish causation, the distinct impact of SP-associated mutations on γ-secretase function, resulting in elevated Aβ43 production, suggests that mutation-specific mechanisms may underlie clinical heterogeneity in ADAD, with potential implications for biomarker and translational research.},
}

Humans
*Alzheimer Disease/genetics/complications/metabolism
Presenilin-1/genetics
*Paraparesis, Spastic/genetics/metabolism
*Amyloid beta-Peptides/metabolism/genetics
Phenotype
Mutation/genetics
Male
Female
*Peptide Fragments/metabolism

@article {pmid41299186,
year = {2025},
author = {Targett, IL and Pring, K and Valiente, AIM and Qualtrough, D and Conway, ME and Crompton, LA and Craig, TJ},
title = {Chronic Fatty Acid Exposure Disrupts SH-SY5Y and Neuronal Differentiation and Is a Potential Link Between Type-2 Diabetes and Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {183},
pmid = {41299186},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/complications ; *Diabetes Mellitus, Type 2/pathology/metabolism ; *Neurons/drug effects/pathology/metabolism ; *Cell Differentiation/drug effects ; Cell Line, Tumor ; *Fatty Acids/toxicity/pharmacology ; Glycogen Synthase Kinase 3 beta/metabolism ; Neurogenesis/drug effects ; Insulin/metabolism ; Signal Transduction/drug effects ; Phosphorylation/drug effects ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, for which there is no curative treatment and few disease-modifying therapies. The vast majority of AD is late onset (LOAD) without a specific genetic cause, although many genetic and non-genetic risk factors have been identified. One of the most significant modifiable risk factors is diet/lifestyle, with type-2 diabetes mellitus (T2DM) increasing LOAD risk by over 50%. Despite the epidemiological data, the reasons for this link are not understood. Here, we investigated whether altered free fatty acid (FFA) levels seen in T2DM can adversely affect neuronal differentiation, a crucial stage in adult hippocampal neurogenesis (AHN), which is defective in LOAD. We show that chronic exposure of the neuroblastoma cell line, SH-SY5Y to T2DM-relevant levels of the FFAs, oleate and palmitate, profoundly affects the differentiation of these cells. This effect is particularly pronounced for the saturated FFA, palmitate, resulting in neuronal cells of altered morphology, lacking expression of key synaptic markers. We further demonstrate that this exposure dysregulates insulin signalling, GSK3β activity, CDK5 levels and CREB phosphorylation. Crucially, these effects were only observed on exposure during differentiation and can be partially replicated in hiPSC-derived forebrain neurones. Although APP expression is increased by palmitate exposure, there was no increase in secreted or intracellular Aβ, and tau phosphorylation was reduced, implying that these defects are separate from the classical hallmarks of AD. We conclude that long-term, chronic exposure of differentiating neurones induces pathological changes that may explain the link between T2DM and LOAD.},
}

Humans
*Alzheimer Disease/pathology/metabolism/complications
*Diabetes Mellitus, Type 2/pathology/metabolism
*Neurons/drug effects/pathology/metabolism
*Cell Differentiation/drug effects
Cell Line, Tumor
*Fatty Acids/toxicity/pharmacology
Glycogen Synthase Kinase 3 beta/metabolism
Neurogenesis/drug effects
Insulin/metabolism
Signal Transduction/drug effects
Phosphorylation/drug effects

@article {pmid41299145,
year = {2025},
author = {Hosseini, E and Sahraian, MA and Negah, SS},
title = {Unlocking the Therapeutic Potential of RGMa: A New Frontier in Neurological Disorder Treatment.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {186},
pmid = {41299145},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy/therapy ; *Nerve Tissue Proteins/metabolism ; GPI-Linked Proteins/metabolism ; },
abstract = {Finding new biomolecules to target upstream signaling in neurological disorders is a state-of-the-art research strategy. Axon guidance molecules (AGMs) play vital roles in development; however, evidence suggests that these molecules are involved in the pathogenesis of several neurological diseases. Recent studies have shown that repulsive guidance molecule A (RGMa), a member of AGMs, can be targeted as a novel therapeutic option. This molecule has been implicated in several diseases, and inhibiting it improves the outcomes. For example, in various pathological conditions such as multiple sclerosis, neuromyelitis optica, optic nerve crush model, focal cerebral ischemia, traumatic brain injury, and vascular dementia the expression of RGMa is significantly elevated. RGMa has been detected on amyloid plaques and in the glial scar in brains impacted by Alzheimer's disease. Furthermore, RGMa is elevated by activated astrocytes after exposure to TGFβ. Since the role of RGMa in the development of neurological disorders is crucial, inhibiting RGMa can lead to positive outcomes such as axonal regeneration, neuronal repair, and behavioral improvement. Our review explores the impact of RGMa and outlines the positive results achieved by targeting it in preclinical studies. Based on this information, it is clear that RGMa has significant potential as both a predictive biomarker and a therapeutic option.},
}

Humans
Animals
*Nervous System Diseases/metabolism/drug therapy/therapy
*Nerve Tissue Proteins/metabolism
GPI-Linked Proteins/metabolism

@article {pmid41299112,
year = {2025},
author = {Shahrukh, M and Adil, M and Hasan, N and Ahmad, FJ},
title = {Development of sustained release injectable phospholipid-based phase transition gel matrixed with Piracetam and cannabidiol loaded nanoemulsion for amelioration of Alzheimer's therapy.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {41299112},
issn = {2190-3948},
support = {09/0591(16126)/2022-EMR-I//Council of Scientific and Industrial Research, India/ ; },
abstract = {Alzheimer's disease (AD) is an incurable neurological disorder and the primary cause of dementia globally, yet therapeutic options remain limited by poor drug efficacy, low patient adherence, and the restrictive blood-brain barrier (BBB), which prevents over 98% of small molecules from reaching the brain. Piracetam (PIRA), a nootropic agent, and cannabidiol (CBD), a neuroprotective compound, have shown potential in addressing AD-related oxidative stress, inflammation, and neurotransmitter imbalance. However, both drugs exhibit short plasma half-lives, requiring frequent dosing that may reduce patient compliance. To address these challenges, we developed a sustained-release phospholipid phase-transition gel (PPTG) depot incorporating a PIRA-CBD nanoemulsion. A combination index study demonstrated potent synergy at a 1:5 CBD: PIRA ratio. Optimization of the nanoemulsion was carried out using a Box-Behnken design, which explored oil concentration (Capryol[®] 90), Smix (Tween 20: Cremophor ELP), and stirring speed as key variables. A mean particle size of 137.8 nm, a PDI of 0.155, and a zeta potential of -7.587 mV were all observed in the formulation that was optimized. Upon subcutaneous injection, the PPTG showed excellent injectability and formed a stable depot in vivo, as confirmed by gamma scintigraphy. In vitro studies revealed sustained release of 90.538 ± 2.62% PIRA and 87.202 ± 2.16% CBD over 96 h, compared to rapid release from the drug solution. This study introduces a novel phospholipid-based phase-transition gel depot incorporating PIRA-CBD nanoemulsion, which provides sustained, targeted brain delivery to enhance therapeutic efficacy and improve patient compliance in Alzheimer's disease management.},
}

@article {pmid41299092,
year = {2025},
author = {Wang, Y and Xiao, S and Liu, B and Jiang, R and Liu, Y and Hang, Y and Chen, L and Chen, R and Vitiello, MV and Bennett, D and Wang, B and Lv, J and Yu, C and Haslam, DE and Zheng, Q and Gerszten, RE and Bao, Y and Shi, J and Xie, J and Lu, L and Li, L and van Duijn, CM and Wang, DD and Chen, Z and Chan, AT},
title = {Organ-specific proteomic aging clocks predict disease and longevity across diverse populations.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {41299092},
issn = {2662-8465},
abstract = {Aging and age-related diseases share convergent pathways at the proteome level. Here, using plasma proteomics and machine learning, we developed organismal and ten organ-specific aging clocks in the UK Biobank (n = 43,616) and validated their high accuracy in cohorts from China (n = 3,977) and the USA (n = 800; cross-cohort r = 0.98 and 0.93). Accelerated organ aging predicted disease onset, progression and mortality beyond clinical and genetic risk factors, with brain aging being most strongly linked to mortality. Organ aging reflected both genetic and environmental determinants: brain aging was associated with lifestyle, the GABBR1 and ECM1 genes, and brain structure. Distinct organ-specific pathogenic pathways were identified, with the brain and artery clocks linking synaptic loss, vascular dysfunction and glial activation to cognitive decline and dementia. The brain aging clock further stratified Alzheimer's disease risk across APOE haplotypes, and a super-youthful brain appears to confer resilience to APOE4. Together, proteomic organ aging clocks provide a biologically interpretable framework for tracking aging and disease risk across diverse populations.},
}

@article {pmid41298994,
year = {2025},
author = {Oriquat, G and Abdulsahib, WK and Jyothi, SR and Nayak, PP and Chauhan, AS and Singla, S and Sead, FF and Polatova, D},
title = {miR-132 and Its Exosomal Form in Alzheimer's Disease: Linking Epigenetic Regulation to Neurodegeneration.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {185},
pmid = {41298994},
issn = {1559-1182},
mesh = {*MicroRNAs/genetics/metabolism ; Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Exosomes/metabolism/genetics ; *Epigenesis, Genetic ; Animals ; *Nerve Degeneration/genetics/pathology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by distinct neuropathological features, including amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, synaptic dysfunction, and chronic neuroinflammation. MicroRNAs (miRNAs), as critical post-transcriptional regulators, exert a profound influence on central nervous system (CNS) function and are increasingly implicated in the pathogenesis of AD. Among these, miR-132 stands out as a brain-enriched miRNA that is consistently downregulated in AD, affecting various aspects of the disease, from Aβ and tau pathologies to synaptic integrity and neuronal survival. Simultaneously, exosomes, nanoscale extracellular vesicles, play a crucial role in intercellular communication and are capable of transporting miRNAs across biological barriers such as the blood-brain barrier. This comprehensive review synthesizes the current understanding of miR-132's intrinsic roles in neuronal health and its dysregulation in AD, elucidates the mechanisms underlying exosome-mediated communication, and explores the complex interplay between exosomal miR-132 and AD pathology. Furthermore, we examine the significant role of epigenetic regulation in modulating miR-132 expression and its broader implications for neurodegeneration. By evaluating the diagnostic potential of miR-132 and its exosomal form as non-invasive biomarkers, as well as their promising therapeutic applications, this review underscores the multifaceted importance of miR-132 in AD. Challenges in current research, particularly with regard to the standardization of exosome isolation methods and the complexity of miRNA regulatory networks, are discussed, highlighting the need for future comprehensive studies to translate these findings into effective clinical strategies for AD management.},
}

*MicroRNAs/genetics/metabolism
Humans
*Alzheimer Disease/genetics/pathology/metabolism
*Exosomes/metabolism/genetics
*Epigenesis, Genetic
Animals
*Nerve Degeneration/genetics/pathology