@article {pmid40274681,
year = {2025},
author = {Dhurandhar, Y and Tomar, S and Das, A and Prajapati, JL and Singh, AP and Bodake, SH and Namdeo, KP},
title = {Chronic inflammation in obesity and neurodegenerative diseases: exploring the link in disease onset and progression.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {424},
pmid = {40274681},
issn = {1573-4978},
abstract = {Obesity, a worldwide health emergency, is defined by excessive fat accumulation and significantly impacts metabolic health. In addition to its recognized association with cardiovascular disease, diabetes, and other metabolic illnesses, recent studies have revealed the connection between obesity and neurodegeneration. The main reason for this link is inflammation caused by the growth of fat tissue, which activates harmful processes that affect how the brain works. Fat tissue, particularly the fat around the organs, produces various substances that cause inflammation, such as cytokines (TNF-α, IL-6), adipokines (leptin, resistin), and free fatty acids. These chemicals cause low-grade, persistent systemic inflammation, which is becoming more widely acknowledged as a major factor in peripheral metabolic dysfunction and pathology of the central nervous system (CNS). Inflammatory signals in the brain cause neuroinflammatory reactions that harm neuronal structures, change neuroplasticity, and disrupt synaptic function. When obesity-related inflammation is present, the brain's resident immune cells, known as microglia, become hyperactivated, which can lead to the production of neurotoxic chemicals, which can cause neuronal death. This neuroinflammation exacerbates the negative effects of obesity on brain health and is linked to cognitive decline, Alzheimer's disease, and other neurodegenerative disorders. Moreover, the blood-brain barrier (BBB) exhibits increased permeability during inflammatory states, facilitating the infiltration of peripheral immune cells and cytokines into the brain, hence exacerbating neurodegeneration. Adipose tissue is a source of chronic inflammatory mediators, which are examined in this review along with the molecular pathways that connect inflammation brought on by obesity to neurodegeneration. Additionally, it addresses various anti-inflammatory treatment approaches, including lifestyle modifications, anti-inflammatory medications, and gut microbiota modulation, to lessen the metabolic and neurological effects of obesity. Recognizing the link between obesity and inflammation opens up new opportunities for early intervention and the development of targeted treatments to prevent or alleviate neurodegenerative disorders.},
}

@article {pmid40274471,
year = {2025},
author = {Garbarino, VR and Palavicini, JP and Melendez, J and Barthelemy, NR and He, Y and Kautz, TF and Lopez-Cruzan, M and Mathews, JJ and Xu, P and Zhang, B and Saliba, A and Ragi, N and Sharma, K and Mason, D and Johnson, S and Hendrix, S and Craft, S and Petersen, RC and Espindola-Netto, JM and Xue, A and Tchkonia, T and Kirkland, JL and Salardini, A and Musi, N and Bateman, RJ and Gonzales, MM and Orr, ME},
title = {Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00591},
doi = {10.1016/j.neurot.2025.e00591},
pmid = {40274471},
issn = {1878-7479},
abstract = {Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer's disease (AD). Clinical trials focused on cellular senescence are in early stages and have yet to establish reliable outcome measures reflecting senescent cell burden or response to senolytics, therapeutics that clear senescent cells. Results from the first open-label trial of senolytics, dasatinib plus quercetin (D + Q), in older adults (N = 5) with early AD demonstrated central nervous system penetration of dasatinib and favorable safety and tolerability. Herein, we present exploratory analyses of senescence and AD-associated analytes in blood, cerebrospinal fluid (CSF) and urine from this study in effort to guide biomarker development for future senolytic trials. Immunoassays, mass spectrometry and transcriptomics were performed and changes in analyte levels were assessed from baseline to post-treatment using paired t-tests. Targeted cytokine and chemokine analyses revealed increases in plasma fractalkine and MMP-7 and CSF IL-6 from baseline to post-treatment. Mass spectrometry indicated stable levels of amyloid β and tau proteins in CSF, unchanged urinary metabolites, and modest treatment-associated lipid profile changes. Targeted transcriptomic analysis of peripheral blood mononuclear cells indicated downregulation of inflammatory genes including FOS, FOSB, IL1β, IL8, JUN, JUNB, PTGS2. The levels and treatment responses of the analytes identified here may help inform trial design and outcomes for senolytic studies. Independent validation will be necessary to develop standardized biomarker panels across senolytic trials for AD. ClinicalTrials.gov: NCT04063124.},
}

@article {pmid40274003,
year = {2025},
author = {Huang, L and Zeng, F and Wei, H and Su, T and Su, Y and Ling, Y and Niu, Q and Xu, Q},
title = {SOAT1 dysregulation in astrocytes drives Blood-Brain barrier dysfunction and neuroinflammation in Alzheimer's disease.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bbi.2025.04.032},
pmid = {40274003},
issn = {1090-2139},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that leads to memory loss and cognitive decline, in which blood-brain barrier (BBB) and astrocyte dysfunction are significantly involved. Recent evidence suggests that dysregulation of lipid metabolism in astrocytes contributes to BBB disruption and neuroinflammation in AD. Sterol O-acyltransferase 1 (SOAT1), an enzyme involved in cholesterol esterification, has been implicated in BBB disruption and neuroinflammation, but its specific role in AD remains unclear. This study aimed to investigate the impact of SOAT1 on lipid metabolism, BBB integrity, and neuroinflammation in AD. Using Oil Red O staining of human autopsy brain tissue and reanalysis of publicly available single-nucleus RNA sequencing (snRNA-seq) data, we identified a significant increase in lipid droplet accumulation and lipid metabolism gene expression, particularly in astrocytes, in the brains of AD patients. Furthermore, in vitro BBB models and the 5 × FAD mouse model were used to explore how SOAT1 expression influences BBB function. Our results demonstrated that elevated SOAT1 expression in astrocytes was positively correlated with increased lipid droplet accumulation and compromised BBB integrity. Knockdown of SOAT1 using siRNA or treatment with the SOAT1 inhibitor K604 restored BBB function, reduced neuroinflammation, and improved cognitive function in 5 × FAD mice. These findings suggest that SOAT1 plays a critical role in astrocytic lipid metabolism and BBB dysfunction in AD. Targeting SOAT1 may be a promising therapeutic approach to alleviate neuroinflammation and restore cognitive function in AD patients.},
}

@article {pmid40273674,
year = {2025},
author = {Padhy, DS and Vesmaker, K and Banerjee, S},
title = {Neuroprotective potential of tranilast in streptozotocin-induced sporadic Alzheimer's disease model targeting TXNIP-NLRP3 inflammasome pathway.},
journal = {International immunopharmacology},
volume = {156},
number = {},
pages = {114691},
doi = {10.1016/j.intimp.2025.114691},
pmid = {40273674},
issn = {1878-1705},
abstract = {Sporadic Alzheimer's disease (sAD) is a progressive neurodegenerative disorder characterised by oxidative stress, neuroinflammation, mitochondrial dysfunction and cerebral insulin resistance. Even though approximately 95 % of AD cases are reported as sporadic, the exact pathogenesis remains sparse. Tranilast, an analogue of tryptophan metabolite, was initially endowed as an anti-allergic agent and used in multiple inflammatory ailments. Still, the molecular mechanisms targeting sAD are yet to be investigated. In the present study, we investigated the neuroprotective potential of tranilast by performing biochemical, molecular and histopathological assessments using both in vivo and in vitro experimental sAD models. Streptozotocin (STZ; 3 mg/kg) was bilaterally injected on day 1 and 3 through the intracerebroventricular (ICV) route to Sprague Dawley rats for the in vivo model induction. Spontaneous alternation test, novel object recognition test, and passive avoidance test were performed to assess the altered behavioural patterns in animals. Furthermore, human neuroblastoma cells (SHSY5Y) were exposed to STZ (1 mM) and tranilast for 24 h to validate the in vivo results. Three weeks of tranilast (30 and 100 mg/kg, p.o.) treatment improved neurobehavioural anomalies in ICV-STZ-treated rats by halting neuroinflammation and NLRP3 inflammasome activation caused by enhanced reactive oxygen species (ROS) and thioredoxin interaction protein (TXNIP) overexpression. The phosphorylated tau (p-tau S416) level was also increased in the ICV-STZ rat's hippocampus and reversed upon tranilast treatment. A high dose of tranilast (100 mg/kg) treatment sensitised hippocampal insulin signalling in ICV-STZ-treated rats. Furthermore, in cell culture studies, 24-h tranilast (30 and 100 μM) treatment reduced the mitochondrial ROS production and attenuated inflammasome activation in STZ-treated SHSY5Y cells. In summary, the findings of the study proclaim the neuroprotective potential of tranilast in STZ induced model of sAD by modulating the TXNIP-NLRP3 inflammasome pathway.},
}

@article {pmid40272460,
year = {2025},
author = {Jiang, Y and Chen, H and Xu, J and Le, J and Rong, W and Zhu, Z and Chen, Y and Hu, C and Cai, J and Hong, Y and Huang, S and Zheng, M and Zhang, X and Zhou, C and Zhang, J and He, S and Yan, X and Cui, W},
title = {Long-term fucoxanthin treatment prevents cognitive impairments and neuroinflammation via the inhibition of Nogo-A in APP/PS1 transgenic mice.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d4fo05034g},
pmid = {40272460},
issn = {2042-650X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuroinflammation and cognitive impairments. Although short-term treatment with fucoxanthin, a marine carotenoid with anti-neuroinflammatory activity, has been reported to prevent cognitive impairments in scopolamine- and β-amyloid (Aβ)-treated mice, it remains uncertain whether long-term fucoxanthin treatment could produce similar effects in transgenic AD models. Moreover, the anti-neuroinflammatory mechanism of fucoxanthin is still unclear. In this study, long-term treatment with fucoxanthin (15-150 mg kg[-1], twice a week for 20 weeks) significantly prevented cognitive deficits and Aβ-related neuroinflammation in APP/PS1 transgenic mice. In addition, fucoxanthin largely prevented Aβ oligomer-induced secretion of pro-inflammatory cytokines and the activation of BV2 microglial cells. Furthermore, fucoxanthin reduced the increased expression of Nogo-A, a central player in AD pathophysiology, as well as the activation of downstream Rho-associated protein kinase 2 (ROCK2) and nuclear factor kappa-B (NF-κB) pathways in AD models. Most importantly, the inhibition of neuroinflammation by fucoxanthin was not reduced by shRNA-mediated knockdown of Nogo-A, suggesting that fucoxanthin significantly prevented cognitive impairments and neuroinflammation via the inhibition of Nogo-A. These results not only elucidate an anti-neuroinflammatory mechanism of fucoxanthin, but also provide strong support for the development of fucoxanthin as a novel food ingredient or drug for the treatment of AD.},
}

@article {pmid40272264,
year = {2025},
author = {Chen, J and Jang, S},
title = {Top-Rated Health Care and Ease of Access to Medications Linked to Lower Medicare and ADRD Costs.},
journal = {Medical care},
volume = {},
number = {},
pages = {},
doi = {10.1097/MLR.0000000000002140},
pmid = {40272264},
issn = {1537-1948},
abstract = {IMPORTANCE: Little is known about the extent to which patient self-perception of care experience is associated with costs, especially for people with Alzheimer disease and related dementias (ADRD).

OBJECTIVE: This study explores the relationship between self-reported quality measures and Medicare costs and examines whether the ease of obtaining prescribed medications is associated with reduced overall Medicare costs, focusing on Medicare beneficiaries with ADRD.

In this cross-sectional study, Medicare Beneficiary Summary File data from 2018, 2019, and 2021 were linked to the Medicare Consumer Assessment of Health Care Providers and Systems (CAHPS) Survey using beneficiary IDs. The study sample included community-dwelling Medicare fee-for-service beneficiaries.

EXPOSURES: Five quality measures were used as key exposure variables: (1) beneficiary's rating on health care, (2) ease of getting care/tests/treatment through the health plan, (3) whether the doctor always explained, listened, respected, and spent enough time with the patient, (4) ease of obtaining prescribed medications, and (5) whether doctor always talked about all the prescription medicines the beneficiary was taking.

MAIN OUTCOME AND MEASURE: Annual total Medicare payments per person.

RESULTS: The study included 230,617 Medicare FFS beneficiaries aged 65 and older, including 16,452 beneficiaries with ADRD. Among the total beneficiaries, 53% were females (vs. 56% of ADRD beneficiaries), with a mean (SD) age of 75.8 (SD 7.27) years [vs. 82.5 (SD 7.97) years for ADRD beneficiaries]. Fully adjusted analyses showed significant negative associations between quality measures and total per-capita payments, with more pronounced cost reductions among patients with ADRD. Specifically, patients with ADRD who reported it was always easy to get care had reductions of $1,922.0 (95% CI, -$3304.8 to -$539.2), while those who reported it was always easy to get prescribed medications had reductions of $2964.5 (95% CI, -$4518.8 to -$1410.1). In addition, beneficiaries who reported that doctors always discussed the medicines experienced cost reductions of $2299.7 (95% CI, -$3800.5 to -$799.0) in medicare costs.

CONCLUSION AND RELEVANCE: Our findings suggest that high-quality care is not necessarily associated with high costs. Meanwhile, focusing on the ease of access to needed care, obtaining prescription drugs, and effective communication about medication is critical in improving care quality while reducing costs.},
}

@article {pmid40271493,
year = {2025},
author = {Nong, W and Chen, X and Chen, Y and Feng, X and Kong, W and Chi, R and Yan, L and Wei, Z},
title = {Natural polyphenol mangiferin delays neuronal cell senescence by inhibiting neuroinflammation mediated by microglial activation.},
journal = {IBRO neuroscience reports},
volume = {18},
number = {},
pages = {574-591},
doi = {10.1016/j.ibneur.2025.04.006},
pmid = {40271493},
issn = {2667-2421},
abstract = {Extracellular β-amyloid protein (Aβ) plaques are prominent pathological feature of Alzheimer's disease (AD). Aβ oligomers and plaques induce sustained microglial activation via the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/interferon regulatory factor 5 (IRF5) signaling pathway. This microglial activation-mediated neuroinflammation can accelerate neuronal cell senescence. Consequently, the regulation of the AMPK/mTOR/IRF5 pathway presents a potential therapeutic target for AD, as it may inhibit neuroinflammation and delay neuronal cell senescence. Mangiferin, a bioactive natural polyphenol extracted from the leaves of Mangifera indica Linn., has garnered significant attention for its anti-inflammatory properties. However, it remains unclear whether mangiferin can modulate the AMPK/mTOR/IRF5 pathway to inhibit microglial activation-mediated neuroinflammation and delay neuronal cell senescence. This study employed both cellular and animal models of neuronal cell senescence to explore the effects of mangiferin on the regulation of the AMPK/mTOR/IRF5 pathway, aiming to inhibit neuroinflammation and delay neuronal cell senescence in vitro and in vivo. Specifically, SH-SY5Y neuroblastoma cells were subjected to a neuroinflammatory microenvironment induced by Aβ1-42-mediated HMC3 microglial activation to induce neuronal cell senescence in vitro. Additionally, SAMP8 accelerated aging mice were utilized as an aging animal model. The results indicate that mangiferin significantly enhances AMPK phosphorylation in microglial cells, inhibits mTOR activation, and downregulates IRF5 expression. These effects collectively suppress microglial activation and markedly reduce the production of pro-inflammatory cytokines by activated microglia. Consequently, there is a decrease in the proportion of neurons arrested in the G0/G1 phase and a reduction in the number of senescence-associated β-galactosidase (SA-β-gal) positive neurons. Furthermore, mangiferin significantly decreases the expression of neuronal cell senescence markers P16Ink4a and P21Cip1. Collectively, these findings suggest that mangiferin effectively regulates the AMPK/mTOR/IRF5 pathway, inhibits neuroinflammation mediated by microglial activation, and delays neuronal cell senescence. This study underscores the potential of mangiferin for the treatment of neuroinflammation and neurodegenerative diseases.},
}

@article {pmid40271071,
year = {2025},
author = {Luo, H and Wei, S and Fu, S and Han, L},
title = {Role of Achyranthes aspera in neurodegenerative diseases: current evidence and future directions.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1511011},
doi = {10.3389/fphar.2025.1511011},
pmid = {40271071},
issn = {1663-9812},
abstract = {Neurodegenerative diseases are caused by the progressive degeneration of neurons and/or their myelin sheaths, ultimately leading to cognitive and motor dysfunction. Due to their complex pathogenesis and the limited efficacy of therapeutic drugs, these diseases have attracted significant attention. Achyranthes aspera, belongs to family Amaranthaceae, has been extensively used in the traditional and folk medicines for the treatment of various ailments. Modern research has revealed that Achyranthes aspera possesses various pharmacological effects, including cardiocerebrovascular protection, immune regulation, antioxidation, and anti-aging. Furthermore, the neuroprotective effects of Achyranthes aspera have been confirmed by numerous scientific studies. This review focuses on the primary pharmacological effects and mechanisms of Achyranthes aspera in the prevention and treatment of neurodegenerative diseases, as well as their potential application prospects. This review aims to provide insights into the potential clinical applications and research directions of Achyranthes aspera in neurodegenerative diseases.},
}

@article {pmid40271063,
year = {2025},
author = {Gong, K and Zhou, S and Xiao, L and Xu, M and Zhou, Y and Lu, K and Yu, X and Zhu, J and Liu, C and Zhu, Q},
title = {Danggui Shaoyao San ameliorates Alzheimer's disease by regulating lipid metabolism and inhibiting neuronal ferroptosis through the AMPK/Sp1/ACSL4 signaling pathway.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1588375},
doi = {10.3389/fphar.2025.1588375},
pmid = {40271063},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline; recent studies suggest that neuronal ferroptosis plays a key role in its pathogenesis. Danggui Shaoyao San (DSS), a traditional Chinese medicine formula, has shown demonstrated neuroprotective effects, but its precise mechanisms in AD treatment remain unclear. This study aims to investigate the mechanism of DSS in treating AD by inhibiting neuronal ferroptosis, explore whether DSS alleviates AD by suppressing neuronal ferroptosis via the AMPK/Sp1/ACSL4 pathway.

METHODS: Chemical composition of DSS was identified by LC-MS/MS, followed by network pharmacology to predict targets and pathways. Molecular docking assessed binding affinities between DSS compounds and key proteins (AMPK, Sp1, ACSL4). In vivo experiments on APP/PS1 mice evaluated DSS effects on cognitive function, oxidative stress markers, lipid peroxidation, and ferroptosis-related proteins.

RESULTS: Network pharmacology analysis suggested that DSS regulates lipid metabolism and inhibits neuronal ferroptosis via the AMPK pathway. Molecular docking revealed strong binding affinities between DSS compounds and AMPK downstream proteins, Sp1 and ACSL4. In vivo experiments showed that DSS improved cognitive function, enhanced antioxidant capacity, reduced lipid peroxide accumulation, and decreased Fe[2+] content in brain tissue. Furthermore, DSS increased the expression of FTH, p-AMPK, and GPX4 while decreasing Sp1 and ACSL4 levels, thereby inhibiting ferroptosis.

CONCLUSION: DSS alleviates AD symptoms by suppressing neuronal ferroptosis via the AMPK/Sp1/ACSL4 axis, representing a novel lipid metabolism-targeted therapeutic strategy.},
}

@article {pmid40269912,
year = {2025},
author = {Boschen, SL and A Mukerjee, A and H Faroqi, A and E Rabichow, B and Fryer, J},
title = {Research models to study lewy body dementia.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {46},
pmid = {40269912},
issn = {1750-1326},
support = {20A07//Florida Department of Health/ ; R03NS112611//NIH/NIA/ ; Fink Family Career Development Award in Neurology//Fink Family Career Development Award in Neurology/ ; },
mesh = {*Lewy Body Disease/pathology/metabolism ; Humans ; Animals ; *Disease Models, Animal ; Alzheimer Disease/pathology ; *Parkinson Disease/pathology/metabolism ; alpha-Synuclein/metabolism ; },
abstract = {Lewy body dementia (LBD) encompasses neurodegenerative dementias characterized by cognitive fluctuations, visual hallucinations, and parkinsonism. Clinical differentiation of LBD from Alzheimer's disease (AD) remains complex due to symptom overlap, yet approximately 25% of dementia cases are diagnosed as LBD postmortem, primarily identified by the presence of α-synuclein aggregates, tau tangles, and amyloid plaques. These pathological features position LBD as a comorbid condition of both Parkinson's disease (PD) and AD, with over 50% of LBD cases exhibiting co-pathologies. LBD's mixed pathology complicates the development of comprehensive models that reflect the full spectrum of LBD's etiological, clinical, and pathological features. While existing animal and cellular models have facilitated significant discoveries in PD and AD research, they lack specificity in capturing LBD's unique pathogenic mechanisms, limiting the exploration of therapeutic avenues for LBD specifically. This review assesses widely used PD and AD models in terms of their relevance to LBD, particularly focusing on their ability to replicate human disease pathology and assess treatment efficacy. Furthermore, we discuss potential modifications to these models to advance the understanding of LBD mechanisms and propose innovative research directions aimed at developing models with enhanced etiological, face, predictive, and construct validity.},
}

*Lewy Body Disease/pathology/metabolism
Humans
Animals
*Disease Models, Animal
Alzheimer Disease/pathology
*Parkinson Disease/pathology/metabolism
alpha-Synuclein/metabolism

@article {pmid40269061,
year = {2025},
author = {Campagna, J and Chandra, S and Teter, B and Cohn, W and Pham, J and Kim, YS and Jagodzinska, B and Vadivel, K and Alam, P and Bilousova, T and Young, M and Elias, C and Marcucci, J and Flacau, I and Jackman, A and Padder, S and Wi, D and Zhu, C and Spilman, P and Jung, ME and Bredesen, DE and John, V},
title = {Discovery of an ApoE4-targeted small-molecule SirT1 enhancer for the treatment of Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {14028},
pmid = {40269061},
issn = {2045-2322},
support = {AG051386-01/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism/genetics ; Animals ; *Apolipoprotein E4/metabolism/genetics ; *Sirtuin 1/metabolism/genetics ; Humans ; Mice ; Disease Models, Animal ; Neurons/metabolism/drug effects ; Promoter Regions, Genetic ; Mice, Transgenic ; },
abstract = {Decreased expression of sirtuin 1 (SirT1) has been implicated in Alzheimer's disease (AD), and as we previously reported, is related to transcriptional repression by the major risk factor for sporadic AD, apolipoprotein E4 (ApoE4). Herein we describe the discovery of an orally brain-permeable small-molecule, DDL-218, that enhanced SirT1 in ApoE4-expressing neuronal cells and a murine AD model. DDL-218 increased the transcription factor NFYb resulting in upregulation of PRMT5. Mechanistic and modeling studies show that binding of ApoE4 to the SirT1 gene promoter can be displaced by PRMT5 leading to increased SirT1 transcription. DDL-218 treatment elicited improvement in memory in the AD model, suggesting that DDL-218 enhancement of neurotrophic SirT1 in the brain has potential to modulate neuronal activity that may clinically provide an improvement in cognitive function and complement the current anti-Aβ antibody monotherapy. Our findings support further development of DDL-218 as a novel ApoE4-targeted therapeutic candidate for AD.},
}

*Alzheimer Disease/drug therapy/metabolism/genetics
Animals
*Apolipoprotein E4/metabolism/genetics
*Sirtuin 1/metabolism/genetics
Humans
Mice
Disease Models, Animal
Neurons/metabolism/drug effects
Promoter Regions, Genetic
Mice, Transgenic

@article {pmid40268841,
year = {2025},
author = {Ahmad, S and Ahmad, L and Adil, M and Sharma, R and Khan, S and Hasan, N and Aqil, M},
title = {Emerging nano-derived therapy for the treatment of dementia: a comprehensive review.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {40268841},
issn = {2190-3948},
abstract = {Dementia includes a variety of neurodegenerative diseases that affect and target the brain's fundamental cognitive functions. It is undoubtedly one of the diseases that affects people globally. The ameliorating the disease is still not known; the symptoms, however, can be prevented to an extent. Dementia encompasses Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia, mixed dementia, and various other diseases. The aggregation of β-amyloid protein plaques and the formation of neurofibrillary tangles have been concluded as the foremost cause for the onset of the disease. As the cases climb, new neuroprotective methods are being developed in the form of new drug delivery systems that provide targeted delivery. Herbal drugs like Ashwagandha, Brahmi, and Cannabis have shown satisfactory results by not only treating the symptoms but have also been shown to reduce and ameliorate the formation of amyloid plaque formation. This article explores the intricate possibilities of drug delivery and the absolute use of herbal drugs to target neurodegenerative diseases. The various possibilities of nanotechnology currently available with new emerging techniques are also discussed.},
}

@article {pmid40268467,
year = {2025},
author = {Tomita, K and Nakashima, KI and Yamaguchi, E and Itoh, A and Inoue, M},
title = {Dual Anti-inflammatory Actions of a Novel Retinoid X Receptor Agonist Derived from a Natural Compound in Microglial Cells.},
journal = {Biological & pharmaceutical bulletin},
volume = {48},
number = {4},
pages = {440-449},
doi = {10.1248/bpb.b25-00037},
pmid = {40268467},
issn = {1347-5215},
mesh = {*Microglia/drug effects/metabolism ; *Retinoid X Receptors/agonists ; Animals ; *Anti-Inflammatory Agents/pharmacology ; Mice ; Lipopolysaccharides/pharmacology ; Cell Line ; Nitric Oxide Synthase Type II/metabolism/genetics ; *Biphenyl Compounds/pharmacology ; Bexarotene/pharmacology ; },
abstract = {Microglia-mediated neuroinflammation plays a critical role in the onset and progression of Alzheimer's disease. In a previous study, we synthesized 6-hydroxy-3'-propyl-[1,1'-biphenyl]-3-propanoic acid (6OHA) based on the structure of magnaldehyde B, a natural compound that our group identified as a retinoid X receptor (RXR) agonist. However, its potential effects on inflammation in microglial cells remain unexplored. In this study, we specifically focused on the early-phase inflammatory responses to lipopolysaccharide (LPS) and evaluated the inhibitory effects of 6OHA on BV-2 microglial cells following 2 h of LPS exposure. Similar to the existing RXR agonist bexarotene (Bex), 6OHA treatment (0.1 and 1 μM) resulted in a dose-dependent decrease in the mRNA levels of proinflammatory mediators, including interleukin-1β (Il1b), Il6, and inducible nitric oxide synthase. However, these effects on proinflammatory mediators were effectively abolished by the RXR antagonist UVI3003. Additionally, 6OHA promoted M2 microglia polarization after 24 h of treatment, as evidenced by the increased mRNA levels of the M2 marker genes arginase-1 (Arg1), C-C motif chemokine ligand 6 (Ccl6), Ccl17, and Ccl22. Notably, 6OHA induced a distinct set of M2 microglial markers compared with IL-4, a known M2 microglial inducer. Furthermore, the transcription of Arg1, a key M2 marker gene, is regulated by retinoic acid receptor/RXR heterodimers and the IL-4 signaling pathway. Collectively, 6OHA suppressed the early inflammatory responses to LPS and promoted M2 microglial polarization through a mechanism distinct from that of IL-4. Therefore, RXR agonists, including 6OHA and Bex, may exhibit dual anti-inflammatory effects and serve as novel modulators of neuroinflammation.},
}

*Microglia/drug effects/metabolism
*Retinoid X Receptors/agonists
Animals
*Anti-Inflammatory Agents/pharmacology
Mice
Lipopolysaccharides/pharmacology
Cell Line
Nitric Oxide Synthase Type II/metabolism/genetics
*Biphenyl Compounds/pharmacology
Bexarotene/pharmacology

@article {pmid40268067,
year = {2025},
author = {Wei, C and Liu, J and Wu, B and Shen, T and Fan, J and Lin, Y and Li, K and Guo, Y and Shang, Y and Zhou, B and Xie, H},
title = {Blockage of CCL3 with neutralizing antibody reduces neuroinflammation and reverses Alzheimer disease phenotypes.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bbi.2025.04.034},
pmid = {40268067},
issn = {1090-2139},
abstract = {BACKGROUND: Accumulating evidence indicates that neuroinflammation is involved in the pathogenesis of Alzheimer's disease (AD). According to RNA sequencing and quantitative PCR (qPCR), we found that chemokine CCL3 mRNA expression was abnormally upregulated in the brains of AD transgenic mice. Moreover, the levels of CCL3 in the serum of AD patients were significantly elevated and negatively correlated with their cognitive abilities. However, the role of CCL3 in AD neuroinflammation and pathological damages remains elusive.

METHODS: Using behavioral, histological, and biochemical methods, outcomes of CCL3 antibody treatment on neuropathology and cognitive deficits were studied in the APPswe/PS1dE9 mice.

RESULTS: In the present study, we reported that CCL3 protein expression was increased in the APPswe/PS1dE9 mice, whereas blockage of CCL3 with neutralizing antibody potently inhibited CCL3 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, CCL3 antibody significantly improved the learning and memory abilities of APPswe/PS1dE9 mice. In addition, CCL3 antibody treatment decreased cerebral amyloid-β (Aβ) levels and plaque burden via inhibiting amyloid precursor protein (APP) processing by reducing beta-site APP cleaving enzyme 1 (BACE1) expression in the APPswe/PS1dE9 mice. We also found that CCL3 antibody treatment alleviated neuroinflammation and reduced synaptic defects in the APPswe/PS1dE9 mice. Furthermore, the activated NF-κB signaling pathway in APPswe/PS1dE9 mice was inhibited by CCL3 antibody treatment.

CONCLUSIONS: Collectively, our findings provide evidence that CCL3 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD.},
}

@article {pmid40267294,
year = {2025},
author = {Jiang, H and Xiao, Z and Saleem, K and Zhong, P and Li, L and Chhetri, G and Li, P and Jiang, Z and Yan, Z and Feng, J},
title = {Generation of human induced pluripotent stem cell-derived cortical neurons expressing the six tau isoforms.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251334831},
doi = {10.1177/13872877251334831},
pmid = {40267294},
issn = {1875-8908},
abstract = {BackgroundThe alternative splicing (AS) of MAPT, which encodes Tau, in the adult human brain produces six major isoforms that play critical roles in the pathogenesis of tauopathies including Alzheimer's disease. Previous efforts have failed to differentiate human induced pluripotent stem cells (hiPSCs) to cortical neurons expressing the six isoforms of Tau.ObjectiveWe aim to develop a differentiation method capable of producing the six Tau isoforms in hiPSC-derived cortical neurons.MethodsWe searched for the optimal concentration, duration and treatment window of morphogens in the differentiation of hiPSCs through embryoid bodies (EBs) to dorsal forebrain neuroepithelial cells then to cortical neurons.ResultsThe combined inhibition of WNT, SHH, and SMAD signaling in EBs generated neuroepithelial cells expressing appropriate dorsal forebrain markers, while suppressing ventral, midbrain, and hindbrain genes. Further differentiation in neurogenic and neurotrophic factors produced MAP2[+] neurons at day 18. The iPSC-derived neurons expressed markers of all cortical layers and exhibited synapse formation and synaptic physiology. In addition, MAP2[+] neurons and mitotic cells expressing radial glial markers formed aggregates that could be dissociated to produce mature neurons with similar properties. Most importantly, the six Tau isoforms were expressed from day 80 in a developmentally regulated manner, modeling the situation in human brains on an accelerated timeline.ConclusionsThis chemically defined differentiation method produces a key hallmark of mature human cortical neurons by expressing the six main splicing isoforms of Tau. It will greatly facilitate disease modeling and therapeutic discovery for many human brain disorders involving cortical neurons.},
}

@article {pmid40267292,
year = {2025},
author = {Wu, X and Yang, Q and Xie, Y and Xia, L and Li, J and An, W and Lu, X},
title = {Drug-targeted Mendelian randomization analysis combined with transcriptome sequencing to explore the molecular mechanisms associated with cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251335891},
doi = {10.1177/13872877251335891},
pmid = {40267292},
issn = {1875-8908},
abstract = {BackgroundCurrent therapies for cognitive impairment, including Alzheimer's disease (AD) and mild cognitive impairment, are limited by a lack of universal treatment and adverse effects associated with polypharmacy. Investigating genetic and molecular mechanisms underlying cognitive decline is critical for the development of targeted therapeutics.ObjectiveTo identify causal genes and potential therapeutic targets for cognitive impairment through integrative genomic analyses.MethodsGenome-wide association study data on cognitive impairment were combined with the expression quantitative trait loci (eQTL) data from the eQTLGen consortium. Mendelian randomization (MR) and colocalization analyses were employed to infer causal relationships. Gene Set Enrichment Analysis and Gene Set Variation Analysis evaluated the pathway and functional differences. Immune cell infiltration patterns and the immunometabolic pathways were assessed, followed by drug target prediction.ResultsMR analysis identified seven gene-eQTL pairs significantly associated with cognitive impairment. SMR colocalization prioritized three key genes: HNMT (histamine metabolism), TNFSF8 (inflammatory signaling), and S1PR5 (sphingolipid signaling). HNMT, TNFSF8, and S1PR5 had 39, 24, and 30 predicted targeted drugs, respectively, including arsenic trioxide, aspirin, and immunomodulators.ConclusionsThis study implicates HNMT, TNFSF8, and S1PR5 as potential therapeutic targets for cognitive impairment. Further validation is required to confirm their clinical relevance.},
}

@article {pmid40267289,
year = {2025},
author = {Jeong, H and Kim, D and Na, S and Kim, B and Oh, JK and Choi, EK and Yoon, S and Bikson, M and Chung, YA and Song, IU},
title = {Repeated neuromodulation with low-intensity focused ultrasound in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333614},
doi = {10.1177/13872877251333614},
pmid = {40267289},
issn = {1875-8908},
abstract = {BackgroundLow-intensity focused ultrasound (LIFU), a non-invasive targeted brain stimulation technology, has shown promise for therapeutic applications in Alzheimer's disease (AD) patients. Despite its potential, the implications of repeated LIFU neuromodulation in AD patients remain to be investigated.ObjectiveThis pilot study evaluated the safety and potential to improve cognition and functional connectivity following repeated LIFU treatment in AD patients.MethodsTen early-stage AD patients underwent six sessions of neuronavigation-guided LIFU targeting the left dorsolateral prefrontal cortex (DLPFC) within 2-3 weeks, alongside ongoing standard pharmacotherapy. Neuropsychological assessments and resting-state functional magnetic resonance imaging were performed at baseline and eight weeks post-treatment.ResultsMemory performance (p = 0.02) and functional connectivity between the left DLPFC and both the left perirhinal cortex and left dorsomedial prefrontal cortex (corrected p < 0.05) significantly improved from baseline. Additionally, enhancements in memory performance were positively correlated with increases in functional connectivity of the left DLPFC with the left perirhinal cortex (Kendall's tau = 0.56, p = 0.03). No adverse events were reported during the LIFU treatments or at the subsequent follow-up.ConclusionsLIFU may have the therapeutic potential to enhance both brain network connectivity and memory functions in AD patients. Our results provide a basis for further research, including randomized sham-controlled trials and optimization of stimulation protocols, on LIFU as a supplementary or alternative treatment option for AD.Trial registrationClinical Research Information Service, KCT0008169, Registered on 10 February 2023.},
}

@article {pmid40267280,
year = {2025},
author = {Li, J and Zhang, F and Eisel, UL},
title = {Adverse events associated with lecanemab: A disproportionality analysis of data from the FDA adverse event reporting system.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251333084},
doi = {10.1177/13872877251333084},
pmid = {40267280},
issn = {1875-8908},
abstract = {BackgroundLecanemab, a monoclonal antibody targeting amyloid-β plaques, is FDA-approved for early Alzheimer's disease (AD) treatment. However, safety data from daily clinical practice is limited.ObjectiveThis study aims to assess the adverse events (AEs) linked to lecanemab using the FDA Adverse Event Reporting System (FAERS) to inform better safety management.MethodsA retrospective pharmacovigilance study was conducted using FAERS data from Q1 2023 to Q2 2024. Disproportionality analysis, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), was applied to evaluate AEs where lecanemab was the primary suspect drug.ResultsFrom Q1 2023 to Q2 2024, 917 AEs related to lecanemab were recorded in the FAERS database, with 67.2% of patients aged between 65 and 85 years and 54.5% involving women. Disproportionality analysis identified significant AEs across 22 organ systems, particularly nervous system and psychiatric disorders. Common AEs included headache, amyloid-related imaging abnormalities, and infusion-related reactions, while sleep-related issues like somnolence, abnormal dreams, and poor-quality sleep were notable. Median onset time was 48 days, with serious outcomes in 14.3% of cases, including 70 hospitalizations and 15 deaths.ConclusionsThis pharmacovigilance analysis confirms known AEs of lecanemab and highlights new safety concerns, particularly its impact on sleep. These findings underscore the importance of ongoing monitoring and research to enhance lecanemab's safety profile in AD treatment. However, due to the limitations of FAERS, our analysis is imperfect in terms of important AEs such as therapy-related brain loss and death.},
}

@article {pmid40267187,
year = {2025},
author = {Guillaud, L and Garanzini, A and Zakhia, S and De la Fuente, S and Dimitrov, D and Boerner, S and Terenzio, M},
title = {Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.},
journal = {Science advances},
volume = {11},
number = {17},
pages = {eadq6077},
doi = {10.1126/sciadv.adq6077},
pmid = {40267187},
issn = {2375-2548},
mesh = {*Adenosine Triphosphate/metabolism ; Humans ; Animals ; *Protein Aggregation, Pathological/metabolism/pathology ; Mice ; *Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Axons/metabolism ; Viscosity ; Mitochondria/metabolism ; Protein Aggregates ; Parkinson Disease/metabolism/pathology ; DNA-Binding Proteins/metabolism ; Alzheimer Disease/metabolism/pathology ; },
abstract = {Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) condensed and underwent ATP-dependent liquid phase separation in vitro. Human inducible pluripotent stem cell-derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.},
}

*Adenosine Triphosphate/metabolism
Humans
Animals
*Protein Aggregation, Pathological/metabolism/pathology
Mice
*Neurons/metabolism
Induced Pluripotent Stem Cells/metabolism
Amyotrophic Lateral Sclerosis/metabolism/pathology
*Axons/metabolism
Viscosity
Mitochondria/metabolism
Protein Aggregates
Parkinson Disease/metabolism/pathology
DNA-Binding Proteins/metabolism
Alzheimer Disease/metabolism/pathology

@article {pmid40266568,
year = {2025},
author = {Rodríguez-Mansilla, J and Chamizo-Gallego, P and González-Sánchez, B and Garrido-Ardila, EM and Torres-Piles, S and Rodríguez-Mansilla, MJ and De Toro-García, Á and Jiménez-Palomares, M},
title = {Virtual reality as a complementary therapy in the rehabilitation of balance and gait disorders in patients with mild cognitive impairment and Alzheimer's disease: Systematic review.},
journal = {Clinical rehabilitation},
volume = {},
number = {},
pages = {2692155251328619},
doi = {10.1177/02692155251328619},
pmid = {40266568},
issn = {1477-0873},
abstract = {ObjectiveTo analyse the benefits of virtual reality in the management of balance and gait disorders in people with Alzheimer's disease and cognitive impairment.Data sourcesPubMed, PEDro, Cochrane Library, Science Direct, Google Scholar and Epistemonikos.Review methodThis study is a systematic review (PROSPERO Registration number: CRD42023486083). The inclusion criteria were: randomised, cross-sectional, quasi-experimental controlled clinical trials involving patients diagnosed with mild cognitive impairment, dementia and Alzheimer's disease with a score of ≤23 on the MMSE test and age ≥60 years, and interventions conducted with virtual reality and conventional physiotherapy for the treatment of balance and gait disorders. The methodological quality and risk of bias assessment was performed with the PEDro scale.Results12 studies were included in the review (n = 476). Three studies applied virtual reality to both experimental and control groups, six applied virtual reality to the experimental group and conventional physiotherapy to the control, and three investigations applied virtual reality to the experimental group and no treatment to the control group. Virtual reality based rehabilitation significantly improved balance and gait, as well as cognitive level, functionality, postural control and mood of the patients compared to those participants who received conventional physiotherapy or no treatment.ConclusionStudies suggest that interventions based on virtual environments in older adults with early Alzheimer's disease can improve balance and gait impairments, postural control and executive function, delaying the deterioration caused by the disease. Furthermore, this therapy has a positive impact on cognitive and motivational performance in these patients.},
}

@article {pmid40266549,
year = {2025},
author = {Kakeda, S and Miki, Y and Kudo, K and Mori, H and Tokumaru, AM and Abe, O and Aoki, S and , },
title = {Practical brain MRI guidelines for anti-Aβ antibody treatment in early symptomatic Alzheimer's disease.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {40266549},
issn = {1867-108X},
abstract = {PURPOSE: These guidelines aim to support magnetic resonance imaging (MRI) diagnosis in patients receiving anti-amyloid β (Aβ) antibody treatment without restricting treatment eligibility.

MATERIALS AND METHODS: These guidelines were collaboratively established by Japan Radiological Society, The Japanese Society of Neuroradiology, and Japanese Society for Magnetic Resonance in Medicine by reviewing existing literature and the results of clinical trials.

RESULTS: Facility standards should comply with the "Optimal Use Promotion Guidelines" of Japan, and physicians should possess comprehensive knowledge of amyloid-related imaging abnormalities (ARIA) and expertise in brain MRI interpretation. The acquisition of knowledge regarding amyloid-related imaging abnormalities, brain MRI, anti-Aβ antibody introduction, and post-treatment diagnosis are also recommended.

CONCLUSION: These guidelines facilitate the accurate diagnosis and effective management of ARIA; ensure the safe administration of anti-Aβ drugs; and provide a framework for MRI facilities, includes staffing requirements and the use of MRI management systems.},
}

@article {pmid40266407,
year = {2025},
author = {Sharma, V and Verma, R and Singh, TG},
title = {Targeting hypoxia-related pathobiology in Alzheimer's disease: strategies for prevention and treatment.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {416},
pmid = {40266407},
issn = {1573-4978},
mesh = {*Alzheimer Disease/metabolism/prevention & control/pathology/therapy ; Humans ; *Hypoxia/metabolism/complications ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Animals ; tau Proteins/metabolism ; Signal Transduction ; Mitochondria/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a neurodegenerative condition characterised by cognitive decline and memory impairment. Recent research highlights the important role of hypoxia, a state of insufficient oxygen availability, in exacerbating AD pathogenesis.

MATERIALS AND METHODS: Through the use of a number of different search engines like Scopus, PubMed, Bentham, and Elsevier databases, a literature review was carried out for investigating the role of hypoxia mediated pathobiology in AD. Only peerreviewed articles published in reputable journals in English language were included. Conversely, non-peer-reviewed articles, conference abstracts, and editorials were excluded, along with studies lacking experimental or clinical relevance or those unavailable in full text.

CONCLUSION: Hypoxia exacerbates core pathological features such as oxidative stress, neuroinflammation, mitochondrial dysfunction, amyloid-beta (Aβ) dysregulation, and hyperphosphorylation of tau protein. These interlinked mechanisms establish a self-perpetuating cycle of neuronal damage, accelerating disease progression. Addressing hypoxia as a modifiable risk factor offers potential for both prevention and treatment of AD. Exploring hypoxia and the HIF signalling pathway may help counteract the neuropathological and symptomatic effects of neurodegeneration.},
}

*Alzheimer Disease/metabolism/prevention & control/pathology/therapy
Humans
*Hypoxia/metabolism/complications
Oxidative Stress
Amyloid beta-Peptides/metabolism
Animals
tau Proteins/metabolism
Signal Transduction
Mitochondria/metabolism

@article {pmid40264328,
year = {2025},
author = {Kumar, L and Rana, R and Shaikh, NK and Thakur, A and Kashyap, S and Aggarwal, V and Jyothiraditya, V},
title = {Alzheimer's Disease and Polymeric Nanocarriers: Synergistic Advances in Targeted Drug Delivery.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266347890250409153450},
pmid = {40264328},
issn = {1873-4294},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a prominent neurodegenerative ailment characterized by the constraints of conventional therapies stemming from insufficient medication transport to the brain. This review examines the function of polymeric nanocarriers (PNCs) in improving therapeutic efficacy for Alzheimer's disease treatment.

METHODS: We analyze the principal obstacles to Alzheimer's disease drug delivery: the blood-brain barrier, the blood-cerebrospinal fluid barrier, and multidrug resistance proteins. The review examines three categories of PNCs: polymeric nanoparticles, polymeric micelles, and dendrimers, and their capacity to surmount these obstacles. Literature investigations used search engines like Pub- Med, Google Scholar, and ScienceDirect.

RESULTS: PNCs exhibit superior drug delivery via better biocompatibility, regulated release, and targeted delivery mechanisms. Recent studies demonstrate the effective delivery of several pharmaceuticals, including rivastigmine and galantamine, resulting in enhanced cognitive outcomes in Alzheimer's disease models. Patent research indicates an increase in innovation for PNC-based Alzheimer's disease treatments.

CONCLUSION: Despite ongoing hurdles in biocompatibility and scalability, PNCs exhibit significant potential to transform Alzheimer's disease treatment by improving medication delivery across biological barriers. Current investigations in nanotechnology and combinatorial medicines indicate a favorable outlook for PNC-based medicinal strategies.},
}

@article {pmid40264324,
year = {2025},
author = {Chauhan, A and Jain, S},
title = {Development of Brain Permeable Drugs and Novel Strategies to Overcome the Brain Barriers for Treatment Purposes.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128386983250410092649},
pmid = {40264324},
issn = {1873-4286},
abstract = {

The Blood-Brain Barrier (BBB), a dynamic and highly selective interface, regulates the exchange of molecules between the circulatory system and the Central Nervous System (CNS). While it protects the brain from toxins and pathogens, it also restricts the delivery of therapeutic agents, posing a significant challenge in treating CNS disorders such as Alzheimer's disease, Parkinson's disease, and glioblastoma. This manuscript explores the structural and functional complexity of the BBB, including the roles of tight junctions, adherens junctions, astrocytes, pericytes, and endothelial cells. It highlights the influence of drug physicochemical properties, such as lipophilicity, molecular weight, and hydrogen bonding, on BBB penetration. Current strategies to enhance drug delivery include nanotechnology-based carriers (liposomes, solid lipid nanoparticles, polymer-based carriers), receptor-mediated transcytosis, and cell-penetrating peptides. Emerging approaches like focused ultrasound with microbubbles, intranasal delivery, and exosome-mediated transport demonstrate significant potential for bypassing BBB constraints. Gene therapy, employing both viral and nonviral vectors, offers promise for addressing genetic CNS disorders. Despite advances, limitations, such as offtarget effects, limited delivery efficiency, and potential toxicity, remain critical barriers to clinical translation. Future research must prioritize multidisciplinary approaches integrating nanotechnology, personalized medicine, and enhanced understanding of BBB biology. Innovations in non-invasive, targeted delivery systems are essential to overcoming existing challenges and enabling effective treatment of CNS disorders. This review underscores the need for further exploration of these technologies to achieve sustained, site-specific drug delivery, thereby advancing therapeutic interventions for neurological diseases. Significance Statement: The blood-brain barrier (BBB) is a critical interface that protects the brain but limits drug delivery, posing challenges in treating CNS disorders. Advancing multidisciplinary approaches and innovative delivery systems is essential to overcome these limitations and enable effective therapies for neurological diseases.},
}

@article {pmid40264302,
year = {2025},
author = {Durosini, E and Anyanwu, M and Vendrame, T and Gianoncelli, A and Ribaudo, G},
title = {Mechanistic investigation on compounds from Amorpha fruticosa L. targeting acetylcholinesterase.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/14786419.2025.2495856},
pmid = {40264302},
issn = {1478-6427},
abstract = {Acetylcholinesterase (AChE) is the enzyme targeted by drugs used for the symptomatic treatment of cognitive decline associated with Alzheimer's disease. While in vitro data suggest the AChE inhibitory potential of A. fruticosa extracts and components such as rotenoids, in-depth mechanistic investigations are missing. A wide array of computational techniques, including ligand-based approaches, molecular docking, molecular dynamics, and machine learning-assisted toxicity prediction were enrolled in the current study, highlighting the rotenoid 6α,12α-dehydrodeguelin as a promising lead for the development of AChE inhibitors.},
}

@article {pmid40264239,
year = {2025},
author = {Zhang, W and Lukacsovich, D and Young, JI and Gomez, L and Schmidt, MA and Martin, ER and Kunkle, BW and Chen, XS and O'Shea, DM and Galvin, JE and Wang, L},
title = {DNA methylation signature of a lifestyle-based resilience index for cognitive health.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {88},
pmid = {40264239},
issn = {1758-9193},
support = {R01AG062634//US National Institutes of Health/ ; R01AG062634//US National Institutes of Health/ ; R01NS101483//US National Institutes of Health/ ; R61NS135587//US National Institutes of Health/ ; AWD-Neuro TSA-01//University of Miami Team Science Funding Program/ ; AWD-Neuro TSA-01//University of Miami Team Science Funding Program/ ; AWD-Neuro TSA-01//University of Miami Team Science Funding Program/ ; K12TR004555//Miami Clinical and Translational Science Institute/ ; },
mesh = {Humans ; *DNA Methylation ; Male ; Female ; Aged ; *Life Style ; *Resilience, Psychological ; *Cognition/physiology ; Alzheimer Disease/genetics ; Aged, 80 and over ; *Cognitive Dysfunction/genetics ; Cohort Studies ; Epigenesis, Genetic ; },
abstract = {Cognitive resilience (CR) contributes to the variability in risk for developing and progressing in Alzheimer's disease (AD) among individuals. Beyond genetics, recent studies highlight the critical role of lifestyle factors in enhancing CR and delaying cognitive decline. DNA methylation (DNAm), an epigenetic mechanism influenced by both genetic and environmental factors, including CR-related lifestyle factors, offers a promising pathway for understanding the biology of CR. We studied DNAm changes associated with the Resilience Index (RI), a composite measure of lifestyle factors, using blood samples from the Healthy Brain Initiative (HBI) cohort. After corrections for multiple comparisons, our analysis identified 19 CpGs and 24 differentially methylated regions significantly associated with the RI, adjusting for covariates age, sex, APOE ε4, and immune cell composition. The RI-associated methylation changes are significantly enriched in pathways related to lipid metabolism, synaptic plasticity, and neuroinflammation, and highlight the connection between cardiovascular health and cognitive function. By identifying RI-associated DNAm, our study provided an alternative approach to discovering future targets and treatment strategies for AD, complementary to the traditional approach of identifying disease-associated variants directly. Furthermore, we developed a Methylation-based Resilience Score (MRS) that successfully predicted future cognitive decline in an external dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), even after accounting for age, sex, APOE ε4, years of education, baseline diagnosis, and baseline MMSE score. Our findings are particularly relevant for a better understanding of epigenetic architecture underlying cognitive resilience. Importantly, the significant association between baseline MRS and future cognitive decline demonstrated that DNAm could be a predictive marker for AD, laying the foundation for future studies on personalized AD prevention.},
}

Humans
*DNA Methylation
Male
Female
Aged
*Life Style
*Resilience, Psychological
*Cognition/physiology
Alzheimer Disease/genetics
Aged, 80 and over
*Cognitive Dysfunction/genetics
Cohort Studies
Epigenesis, Genetic

@article {pmid40264187,
year = {2025},
author = {Wang, S and Qi, C and Rajpurohit, C and Ghosh, B and Xiong, W and Wang, B and Qi, Y and Hwang, SH and Hammock, BD and Li, H and Gan, L and Zheng, H},
title = {Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {44},
pmid = {40264187},
issn = {1750-1326},
support = {093652/NS/NINDS NIH HHS/United States ; 020670/AG/NIA NIH HHS/United States ; 068031/AG/NIA NIH HHS/United States ; 066606/AG/NIA NIH HHS/United States ; Not applicable//Cure Alzheimer's Fund/ ; A25-1690//Harrington Discovery Institute, University Hospitals/ ; },
mesh = {Animals ; *Epoxide Hydrolases/antagonists & inhibitors/metabolism ; *Microglia/drug effects/metabolism ; *Tauopathies/metabolism/drug therapy/pathology ; Mice ; Disease Models, Animal ; *Neuroprotection/drug effects/physiology ; Homeostasis/drug effects/physiology ; Mice, Knockout ; Humans ; Mice, Transgenic ; Neuroprotective Agents/pharmacology ; },
abstract = {BACKGROUND: The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer's disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood.

METHODS: Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the PS19 mice with Ephx2 (gene encoding sEH) knockout mice. This was followed by single-nucleus RNA-sequencing (snRNA-seq), biochemical and immunohistochemical analysis, and behavioral assessments. Additionally, we examined the effects of the sEH-EET pathway in primary microglia cultures and human induced pluripotent stem cell (iPSC)-derived neurons exhibiting seeding-induced Tau inclusions.

RESULTS: sEH inhibition improved cognitive function, rescued neuronal cell loss, and reduced Tau pathology and microglial reactivity. snRNA-seq revealed that TPPU treatment upregulated genes involved in actin cytoskeleton and excitatory synaptic pathways. Treatment of human iPSC-derived neurons with TPPU enhanced synaptic density without affecting Tau accumulation, suggesting a cell-autonomous neuroprotective effect of sEH blockade. Furthermore, sEH inhibition reversed disease-associated and interferon-responsive microglial states in PS19 mice, while EET supplementation promoted Tau phagocytosis and clearance in primary microglia cultures.

CONCLUSION: These findings demonstrate that sEH blockade or EET augmentation confers therapeutic benefit in neurodegenerative tauopathies by simultaneously targeting neuronal and microglial pathways.},
}

Animals
*Epoxide Hydrolases/antagonists & inhibitors/metabolism
*Microglia/drug effects/metabolism
*Tauopathies/metabolism/drug therapy/pathology
Mice
Disease Models, Animal
*Neuroprotection/drug effects/physiology
Homeostasis/drug effects/physiology
Mice, Knockout
Humans
Mice, Transgenic
Neuroprotective Agents/pharmacology

@article {pmid40263406,
year = {2025},
author = {Slimi, H and Abid, S and Sayadi, M},
title = {Revolutionizing Alzheimer's disease detection with a cutting-edge CAPCBAM deep learning framework.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {13925},
pmid = {40263406},
issn = {2045-2322},
mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; *Deep Learning ; Magnetic Resonance Imaging/methods ; Image Processing, Computer-Assisted/methods ; Neural Networks, Computer ; },
abstract = {Early and accurate diagnosis of Alzheimer's disease (AD) is crucial for effective treatment. While the integration of deep learning techniques for AD classification is not entirely new, this study introduces CAPCBAM-a framework that extends prior approaches by combining Capsule Networks with a Convolutional Block Attention Module (CBAM). In CAPCBAM, standardized preprocessing of MRI images is followed by feature extraction using Capsule Networks, which preserve spatial hierarchies and capture intricate relationships among image features. The subsequent application of CBAM, employing both channel and spatial attention mechanisms, refines the feature maps to highlight the most clinically relevant regions. This dual-attention strategy offers clear advantages over conventional CNN methods, particularly in enhancing model generalization and mitigating information loss due to pooling. On the ADNI dataset, CAPCBAM achieved an impressive accuracy of 99.95%, with precision and recall both at 99.8%, an AUC of 0.99, and an F1-Score of 99.92%. Although the use of Capsule Networks and attention mechanisms has been explored previously, CAPCBAM distinguishes itself by its robust integration of these components. The study's advantages include improved feature extraction, faster convergence, and superior classification performance, making it a promising tool for the early detection of Alzheimer's disease.},
}

*Alzheimer Disease/diagnosis/diagnostic imaging
Humans
*Deep Learning
Magnetic Resonance Imaging/methods
Image Processing, Computer-Assisted/methods
Neural Networks, Computer

@article {pmid40262935,
year = {2025},
author = {Lai, LF and Li, X and Li, HZ and Li, ZM and Liu, L and Zhang, YY and Yang, H and Luo, BY and Yi, W and Xu, NG and Zhao, JY},
title = {[Electroacupuncture improves synaptic plasticity and cognitive dysfunction via down-regulating HDAC3 in mice of Alzheimer's disease].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {50},
number = {4},
pages = {375-383},
doi = {10.13702/j.1000-0607.20240214},
pmid = {40262935},
issn = {1000-0607},
mesh = {Animals ; *Electroacupuncture ; *Alzheimer Disease/therapy/genetics/enzymology/physiopathology/psychology/metabolism ; Mice ; *Neuronal Plasticity ; *Histone Deacetylases/genetics/metabolism ; Humans ; Male ; *Cognitive Dysfunction/therapy/genetics/enzymology/physiopathology/psychology ; Receptors, N-Methyl-D-Aspartate/metabolism/genetics ; Hippocampus/enzymology/metabolism ; Down-Regulation ; Female ; Acupuncture Points ; },
abstract = {OBJECTIVES: To observe the effect of electroacupuncture(EA) on histone deacetylase 3 (HDAC3), synaptic plasticity and N-methyl-D-aspartate (NMDA) receptors in the hippocampus of mice with Alzheimer's disease(AD), so as to explore the underlying mechanism of EA in treatment of AD.

METHODS: 5XFAD mice were randomly divided into EA group, model group and sham-acupuncture group, with 13 mice in both the EA group and the model group, and 7 mice in the sham-acupuncture group. Thirteen wild-type mice from the same litter were taken as the normal control group. The mice in the EA group received EA at "Baihui" (GV20)and "Dazhui" (GV14) for 15 min once daily, 6 times a week for 4 weeks. The mice in the sham-acupuncture group received sham EA, i.e., the needle was inserted into the rubber clay which was placed on the surface of the corresponding acupoints. The novel object recognition(NOR), Y-maze and Morris water maze(MWM) tests were used to observe the cognitive functions of mice. Electrophysiological technique was used to detect long-term potentiation (LTP) of the hippocampal neurons and Western blot was used to detect the relative expressions of HDAC3 and NMDAR-related receptors (NMDAR1, NMDAR2A, NMDAR2B) in the hippocampus.

RESULTS: Compared with the normal control group, 5XFAD mice in the model group showed decreased(P<0.01, P<0.05) preference index for new object recognition, alternative arm ratio (AAR), number of times crossing the original platform, percentage of time and distance traveled in the target quadrant, NMDAR2B, NMDAR2A and NMDAR1 protein expression levels, with prolonged(P<0.01) escape latency, and increased (P<0.05) protein relative expression of HDAC3. At the same time, with high-frequency stimulation, the slope of fEPSP was decreased(P<0.01, P<0.05)in the 5XFAD mice. After EA intervention, comparison between the EA and the model groups revealed that, the preference index for new object recognition, AAR were increased (P<0.01, P<0.05) in the EA group, the escape latency was shortened (P<0.05), and the number of times crossing the platform, percentage of time and distance traveled in the target quadrant, the slope of fEPSP, and the protein relative expressions of NMDAR2B, NMDAR2A and NMDAR1 in the hippocampus were increased (P<0.01, P<0.05), while the protein relative expression of HDAC3 decreased (P<0.01). Compared with sham-acupuncture group, the above indexes improved to different degree in the EA group (P<0.01, P<0.05).

CONCLUSIONS: EA of GV20 and GV14 can restore the impaired LTP and improve the cognitive impairment, which may be related to increasing the expressions of NMDA-related receptor proteins and down-regulating the expression of HDAC3 in the hippocampus of 5XFAD mice.},
}

Animals
*Electroacupuncture
*Alzheimer Disease/therapy/genetics/enzymology/physiopathology/psychology/metabolism
Mice
*Neuronal Plasticity
*Histone Deacetylases/genetics/metabolism
Humans
Male
*Cognitive Dysfunction/therapy/genetics/enzymology/physiopathology/psychology
Receptors, N-Methyl-D-Aspartate/metabolism/genetics
Hippocampus/enzymology/metabolism
Down-Regulation
Female
Acupuncture Points

@article {pmid40262568,
year = {2025},
author = {Tuna, RW and Achmad, NA and Kurniawan, I and Khairiyah, and Asaf, MB and Sapiun, Z and Himawan, A and Dominguez-Robles, J and Aswad, M and Permana, AD},
title = {Development of thermosensitive mucoadhesive gel incorporated lipid microspheres of donepezil for enhanced nose-to-brain delivery.},
journal = {Journal of biomaterials science. Polymer edition},
volume = {},
number = {},
pages = {1-28},
doi = {10.1080/09205063.2025.2492455},
pmid = {40262568},
issn = {1568-5624},
abstract = {Alzheimer's disease (ALZ) is a chronic disease that affects the brain neurons leading to dementia. Donepezil (DPZ), a first-line treatment for ALZ is a potent symptomatic therapeutic agent. However, the oral and transdermal route represents non-targeted delivery, causing various adverse effects. This study presents the successful incorporation of a DPZ-loaded lipid microsphere (DPZ-LM) system into a thermosensitive-mucoadhesive gel (TMG), thereby enhancing the delivery of DPZ through the nose-to-brain route. To optimize the formulations, several evaluations were conducted, resulting in an optimized formulation of LM using Compritol[®] exhibited particle size of 8.75 µm, 98.44% of DPZ entrapped, and 93.40% of DPZ loaded in the system with a sustained release manner in the in vitro studies. The TMG-DPZ-LM was prepared using Pluronic[®] F127 and F68, as the gelling agents, with the addition of sodium alginate, as the mucoadhesive polymer. Following incorporation into TMG-DPZ-LM, the system exhibited excellent physicochemical properties and effective nasal delivery in ex vivo permeation has found that 88.58 ± 12.53 µg/cm[2] and retention studies with a mean concentration of 0.0077 mg of retention DPZ in porcine nasal mucosa. The in vivo pharmacokinetic studies demonstrated that the administration of TMG-DPZ-LM via the nose-to-brain route resulted in a significant (p < 0.05) increase in the Cmax, with 207.24 ± 5.16 µg/cm[3] of DPZ in the brain that exhibited a significantly different profile compared to the other route and formulation. The TMG-DPZ-LM system that was developed in this study was considered to have improved its efficacy in the treatment of ALZ.},
}

@article {pmid40261286,
year = {2025},
author = {Bannon, SM and McCage, S and Walker, K and Brewer, J and Ahmad, N and Cornelius, T and Parker, RA and Dams-O'Connor, K and Dickerson, B and Ritchie, CS and Vranceanu, AM},
title = {Resilient together for dementia: A qualitative study of couples' treatment preferences to address distress early after diagnosis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251332658},
doi = {10.1177/13872877251332658},
pmid = {40261286},
issn = {1875-8908},
abstract = {BackgroundDespite technological advances and earlier and more confident diagnoses, there is a lack of post-diagnosis support for couples navigating the challenges of early dementia. Clinically elevated emotional distress is common for both partners after diagnosis, and interferes with the health, relationships, and adjustment of both partners if not addressed.ObjectiveOur objective was to gather in-depth information on couples' preferences to inform the development of a proposed dyadic intervention addressing emotional distress early (within 6 months) after one partners' receipt of a dementia diagnosis.MethodsWe recruited couples after a recent dementia diagnosis (N = 16 dyads; 32 participants) from a large academic medical center via direct provider referrals for 60-min virtual dyadic interviews. Data were analyzed using a hybrid inductive-deductive approach to thematic analysis.ResultsWe identified themes within 3 a-priori determined domains. For dyadic intervention format (domain 1), couples preferred to participate in sessions together and to have flexible options for telehealth and in-person participation. Preferences for intervention content (domain 2) included information on dementia, skills to reduce distress and promote resiliency, and support to communicate about the diagnosis and related stress. Barriers and facilitators (domain 3) included denial or hesitation, resource constraints, and interests in learning skills and connecting to others.ConclusionsWe gathered comprehensive information that could be used to adapt existing dyadic interventions and to tailor support to match couples' preferences early after dementia diagnoses. Early interventions should prioritize flexible delivery of information and skills to couples to support adaptive coping following dementia diagnoses.},
}

@article {pmid40260186,
year = {2025},
author = {Piñol-Ripoll, G and Salas Carrillo, M and , },
title = {Clinicians' Perspectives of Twice-Weekly Rivastigmine Patches for Alzheimer's Disease Treatment in Spain: The VIITAL 2S Study.},
journal = {Patient preference and adherence},
volume = {19},
number = {},
pages = {1105-1118},
pmid = {40260186},
issn = {1177-889X},
abstract = {PURPOSE: Administration routes and dosage significantly impact Alzheimer's disease (AD) treatment effectiveness, as compliance in older patients depends on interactions between concomitant treatments, complex dosages, adverse effects, or medication tolerance. This study aims to describe patient and caregiver preferences concerning treatment with rivastigmine twice-weekly transdermal patches from the neurologists' and geriatricians' perspectives.

METHODS: VIITAL-2S was an ecological study based on aggregated data. A total of 250 Spanish neurologists and geriatricians answered a survey on the use, adherence, patient and caregiver satisfaction, and safety (skin tolerability) of twice-weekly rivastigmine patches.

RESULTS: Most participating physicians reported having over 11 years of experience in their specialty. According to their responses, patients with AD attending Neurology and Geriatrics were usually in mild-moderate condition, and a mean of 61.4% received rivastigmine. Around 60% of patients lived with a family member, and over 80% had a caregiver, mainly their partner/spouse or other relative. Of note, more than half of patients attending Neurology and nearly 75% of patients in Geriatrics received 4-10 medications daily. Both specialists recommended the transdermal formulation to patients receiving rivastigmine. In 33.8% and 41.0% of patients receiving daily patches, neurologists and geriatricians, respectively, recommended switching to twice-weekly patches, considering higher administration comfort and caregiver preferences. Physicians reported high/very high satisfaction with twice-weekly patches in nearly 80% of patients. Comparing twice-weekly to daily patches, they observed higher comfort, more caregiver satisfaction, and enhanced adherence. Both specialists manifested preferring twice-weekly rivastigmine patches over daily ones, especially to increase caregivers' comfort, for patients without full-week caregiver support, and in cases of poor compliance with previous treatments.

CONCLUSION: Neurologists and geriatricians consider the twice-weekly rivastigmine patch formulation beneficial for AD treatment in terms of treatment compliance, skin tolerability, satisfaction and comfort for patients and caregivers.},
}

@article {pmid40259559,
year = {2025},
author = {Wu, H and Sun, Z and Gan, J and Wen, C and Shi, Z and Liu, S and Ji, Y},
title = {Efficacy of cholinesterase inhibitors treatment in dementia with Lewy bodies: A 3-year follow-up 'real world' study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251330902},
doi = {10.1177/13872877251330902},
pmid = {40259559},
issn = {1875-8908},
abstract = {BackgroundDementia with Lewy bodies (DLB) is the second most common dementia after Alzheimer's disease. Currently, no specific therapeutic agents are available for DLB. However, evidence of cholinergic deficits suggests that enhancing central cholinergic function may be a viable therapeutic approach.ObjectiveTo assess cognitive changes in DLB patients treated with cholinesterase inhibitors (ChEIs) in a real-world setting.MethodsThis retrospective study in a prospective database analyzed data from three dementia clinics between May 2012 and December 2022. Patients with DLB were divided into two groups: those treated with ChEIs and those untreated. Differences in changes in multiple cognitive-related scales between the two groups were analyzed.ResultsThe study included 204 DLB patients, with 133 (65.2%) in the ChEIs group and 71 (34.8%) in the non-ChEIs group. Initial demographic and clinical characteristics were similar between groups. Over time, patients in the ChEIs group showed significantly higher scores on the Mini-Mental State Examination and the Montreal Cognitive Assessment compared to the non-ChEIs group, indicating improved cognitive function. No significant differences were observed in activities of daily living scores.ConclusionsChEIs improved cognitive symptoms in DLB patients in the "real world" study. These findings are consistent with those from a previous small-sample randomized controlled trial. Longitudinal data indicate sustained benefits with continuous ChEIs use in three years. Overall, ChEIs show substantial potential for improving cognitive symptoms in DLB patients.},
}

@article {pmid40258814,
year = {2025},
author = {Chen, J and Chen, H and Wei, Q and Lu, Y and Wang, T and Pang, X and Xing, G and Chen, Z and Cao, X and Yao, J},
title = {APOE4 impairs macrophage lipophagy and promotes demyelination of spiral ganglion neurons in mouse cochleae.},
journal = {Cell death discovery},
volume = {11},
number = {1},
pages = {190},
pmid = {40258814},
issn = {2058-7716},
support = {82071052//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82200642//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32070587//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {The ApoE-ε4 gene is a well-established genetic risk factor for neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis, which are characterized by axonal demyelination in the central nervous system. Recent studies have implicated ApoE-ε4 in age-related hearing loss (ARHL), suggesting a potential role of APOE4 isoform in peripheral nervous system degeneration. However, the role of APOE4 in ARHL are still unclear. In this study, we explored the potential role of APOE4 in axonal demyelination of spiral ganglion neurons (SGNs). ApoE-ε4/ε4 (APOE4) and ApoE-ε3/ε3 (APOE3) mice were used to characterize SGNs. The effect of APOE4 on phagocytosis and autophagy as well as intracellular cholesterol level was evaluated in resident cochlear macrophages (RCMs) and mouse bone marrow-derived macrophages (BMDMs). The results showed that significant axonal demyelination was observed in SGNs of 10-month-old APOE4 mice, accompanied by the presence of myelin debris engulfed by RCMs. Meanwhile, inhibited phagocytosis of myelin debris and impaired lipophagy were detected in APOE4 RCMs and APOE4 BMDMs with an aberrant accumulation of lipid droplets (LDs), which could be reversed by trehalose treatment. This study provided a deep insight into the pathogenesis of APOE4-induced axonal demyelination of SGNs associated with the impaired lipophagy in RCMs, which helped to elucidate the underlying mechanism of ApoE-ε4 in ARHL.},
}

@article {pmid40257938,
year = {2025},
author = {Cont, C and Reinboth, BS and Schütz, C and Stute, N and Galli, A and Schulte, C and Wojtecki, L},
title = {Transcranial Pulse Stimulation for Alzheimer's Patients.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {218},
pages = {},
doi = {10.3791/67176},
pmid = {40257938},
issn = {1940-087X},
mesh = {*Alzheimer Disease/therapy ; Humans ; Magnetic Resonance Imaging/methods ; *Transcranial Direct Current Stimulation/methods/instrumentation ; *Transcranial Magnetic Stimulation/methods/instrumentation ; },
abstract = {Transcranial pulse stimulation (TPS) is a noninvasive neuromodulation therapy with Conformité Européenne (CE) marking for the treatment of Alzheimer's disease (AD). Initial pilot studies have demonstrated promising effects on cognitive function. This article focuses on the procedure for treating patients with AD using an MRI-guided, neuro-navigated TPS device. The protocol to be followed for this is described in detail, including the necessary procedures and device settings. A brief overview of the representative clinical results published to date is also provided. In addition to significant clinical improvements in cognition and affect, adverse events (AE) and possible adverse device events (ADE) are presented to provide safety data. Finally, the method is critically discussed. In the future, randomized controlled trials should be conducted to rule out any placebo effects. There is also currently a lack of long-term studies with a larger number of patients. Despite these unresolved questions, TPS has the potential as an adjunct treatment for Alzheimer's patients when used in a controlled, scientifically guided setting.},
}

*Alzheimer Disease/therapy
Humans
Magnetic Resonance Imaging/methods
*Transcranial Direct Current Stimulation/methods/instrumentation
*Transcranial Magnetic Stimulation/methods/instrumentation

@article {pmid40257754,
year = {2025},
author = {Lazli, L},
title = {Improved Alzheimer Disease Diagnosis With a Machine Learning Approach and Neuroimaging: Case Study Development.},
journal = {JMIRx med},
volume = {6},
number = {},
pages = {e60866},
doi = {10.2196/60866},
pmid = {40257754},
issn = {2563-6316},
abstract = {BACKGROUND: Alzheimer disease (AD) is a severe neurological brain disorder. While not curable, earlier detection can help improve symptoms substantially. Machine learning (ML) models are popular and well suited for medical image processing tasks such as computer-aided diagnosis. These techniques can improve the process for an accurate diagnosis of AD.

OBJECTIVE: In this paper, a complete computer-aided diagnosis system for the diagnosis of AD has been presented. We investigate the performance of some of the most used ML techniques for AD detection and classification using neuroimages from the Open Access Series of Imaging Studies (OASIS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) datasets.

METHODS: The system uses artificial neural networks (ANNs) and support vector machines (SVMs) as classifiers, and dimensionality reduction techniques as feature extractors. To retrieve features from the neuroimages, we used principal component analysis (PCA), linear discriminant analysis, and t-distributed stochastic neighbor embedding. These features are fed into feedforward neural networks (FFNNs) and SVM-based ML classifiers. Furthermore, we applied the vision transformer (ViT)-based ANNs in conjunction with data augmentation to distinguish patients with AD from healthy controls.

RESULTS: Experiments were performed on magnetic resonance imaging and positron emission tomography scans. The OASIS dataset included a total of 300 patients, while the ADNI dataset included 231 patients. For OASIS, 90 (30%) patients were healthy and 210 (70%) were severely impaired by AD. Likewise for the ADNI database, a total of 149 (64.5%) patients with AD were detected and 82 (35.5%) patients were used as healthy controls. An important difference was established between healthy patients and patients with AD (P=.02). We examined the effectiveness of the three feature extractors and classifiers using 5-fold cross-validation and confusion matrix-based standard classification metrics, namely, accuracy, sensitivity, specificity, precision, F1-score, and area under the receiver operating characteristic curve (AUROC). Compared with the state-of-the-art performing methods, the success rate was satisfactory for all the created ML models, but SVM and FFNN performed best with the PCA extractor, while the ViT classifier performed best with more data. The data augmentation/ViT approach worked better overall, achieving accuracies of 93.2% (sensitivity=87.2, specificity=90.5, precision=87.6, F1-score=88.7, and AUROC=92) for OASIS and 90.4% (sensitivity=85.4, specificity=88.6, precision=86.9, F1-score=88, and AUROC=90) for ADNI.

CONCLUSIONS: Effective ML models using neuroimaging data could help physicians working on AD diagnosis and will assist them in prescribing timely treatment to patients with AD. Good results were obtained on the OASIS and ADNI datasets with all the proposed classifiers, namely, SVM, FFNN, and ViTs. However, the results show that the ViT model is much better at predicting AD than the other models when a sufficient amount of data are available to perform the training. This highlights that the data augmentation process could impact the overall performance of the ViT model.},
}

@article {pmid40257689,
year = {2025},
author = {Sharma, A and Mehra, V and Kumar, V and Jain, A and Prakash, H},
title = {Tailoring MAPK Pathways: New Therapeutic Avenues for Treating Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40257689},
issn = {1559-1182},
abstract = {Alzheimer's disease (AD) is irreversible, progressive, and refractory in nature and is managed very poorly clinically due to very limited treatment outcomes. Unfortunately, most of the multiple clinical trials involving AD patients were unsuccessful in improving the disease prognosis. At the cellular level, many signaling pathways have been proposed to be involved in the sterile/refractory behavior of degenerating neurons in AD. Due to the involvement of p38MAPK in the pathogenesis of Alzheimer's disease, numerous investigations have attempted to determine the beneficial effects of MAPK targeting on memory, inflammatory programming of the brain, and synaptic plasticity. In view of this, various clinical trials involving several MAPK inhibitors (with good safety profiles and few side effects) have yielded positive results in AD patients, suggesting that MAPK targeting may be effective for reducing the pathogenesis of AD, but due to selectivity, dosing, and patient stratification, this aspect still needs further development. In view of their selectivity and off-target effects, only a few MAPK inhibitors have been employed in clinical trials against AD, indicating the scope of their development in this area. Therefore, this study focused on MAPK-based interventions as an upcoming and innovative approach for alleviating AD, with a special emphasis on clinical studies.},
}

@article {pmid40257662,
year = {2025},
author = {Zhou, J and Sun, X and Wang, K and Shen, M and Yu, J and Yao, Q and Hong, H and Tang, C and Wang, Q},
title = {What Information do Systemic Pathological Changes Bring to the Diagnosis and Treatment of Alzheimer's Disease?.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {40257662},
issn = {1995-8218},
abstract = {Alzheimer's disease (AD) is regarded as a neurodegenerative disease, and it has been proposed that AD may be a systemic disease. Studies have reported associations between non-neurological diseases and AD. The correlations between AD pathology and systemic (non-neurological) pathological changes are intricate, and the mechanisms underlying these correlations and their causality are unclear. In this article, we review the association between AD and disorders of other systems. In addition, we summarize the possible mechanisms associated with AD and disorders of other systems, mainly from the perspective of AD pathology. Regarding the relationship between AD and systemic pathological changes, we aim to provide a new outlook on the early warning signs and treatment of AD, such as establishing a diagnostic and screening system based on more accessible peripheral samples.},
}

@article {pmid40257023,
year = {2025},
author = {Zheng, Q and Wang, S and Wang, T and Zhang, G},
title = {Efficacy of Stem Cell-derived Extracellular Vesicles in the Treatment of Alzheimer's Disease Model Mice: A Systematic Review and Meta-analysis.},
journal = {Current stem cell research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.2174/011574888X352270250407170235},
pmid = {40257023},
issn = {2212-3946},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that is still incurable. Therapy with stem cell or extracellular vesicles is a promising strategy for AD treatment. Therefore, we evaluated whether stem cell-derived extracellular vesicles could improve cognitive function and pathological features in AD model mice.

METHODS: PubMed, Web of Science, Embase, and The Cochrane Library were searched for studies reporting stem cell-derived extracellular vesicles treatment of AD mice from the establishment of each database to 1st August 2023. SYRCLE was used to assess the risk of bias. The extracted data were analyzed using RevMan 5.4 and Stata 15 software.

RESULTS: 19 studies were included in the analysis. Meta-analysis showed that treatment with stem cell-derived extracellular vesicles significantly improved cognitive performance of AD mice in the Morris water maze test and the novel object recognition test, reduced β-amyloid deposition, alleviated neuroinflammation and decreased levels of the proinflammatory cytokines and glial fibrillary acidic protein (GFAP) in the brain of AD mice. However, stem cell-derived extracellular vesicle did not affect the level of brain phosphorylated tau (p-Tau).

CONCLUSIONS: stem cell-derived extracellular vesicles may promote the degradation of β-amyloid plaques in the brain, regulate immunity and protect nerves, which result in cognitive improvement in AD mice.},
}

@article {pmid40256965,
year = {2025},
author = {Loring, DW and Lah, JJ and Head, EN and Hale, CL and McIntosh, RL},
title = {County Health Departments Facilitate Telehealth Dementia Evaluation: The Georgia Memory Net Collaboration.},
journal = {Telemedicine journal and e-health : the official journal of the American Telemedicine Association},
volume = {},
number = {},
pages = {},
doi = {10.1089/tmj.2024.0580},
pmid = {40256965},
issn = {1556-3669},
abstract = {Objective: To establish partnerships with county public health departments to expand telehealth access for referrals to Georgia Memory Net (GMN), a state-funded program focused on improving the early and accurate diagnosis of Alzheimer's disease and other dementias. Method: Funding from the Coronavirus Aid, Relief, and Economic Security Act, and the Building Our Largest Dementia (BOLD) Infrastructure for Alzheimer's Act supported GMN partnership development with Georgia Department of Public Health county health departments. Results: Telehealth infrastructure, including remote video neurological assessments and neuropsychological testing, is now available in 10 Georgia county health departments. Expansion efforts are in progress to bring telehealth services to additional counties, broadening GMN reach. Conclusion: Telehealth evaluations delivered through county health departments provide an effective platform for expanding access to specialized dementia diagnosis and treatment, particularly in rural and underserved areas, enhancing early detection and care for patients throughout the state.},
}

@article {pmid40256625,
year = {2025},
author = {Wu, Z and Long, W and Yin, Y and Tan, B and Liu, C and Li, H and Ge, S},
title = {Outer membrane vesicles of Porphyromonas gingivalis: recent advances in pathogenicity and associated mechanisms.},
journal = {Frontiers in microbiology},
volume = {16},
number = {},
pages = {1555868},
pmid = {40256625},
issn = {1664-302X},
abstract = {Periodontitis is a chronic infectious inflammatory disease primarily caused by periodontal pathogenic bacteria, which poses a significant threat to human health. The pathogenic mechanisms associated with Porphyromonas gingivalis (P. gingivalis), a principal causative agent of periodontitis, are particularly complex and warrant thorough investigation. The extensive array of virulence factors released by this bacterium during its growth and pathogenesis not only inflicts localized damage to periodontal tissues but is also intricately linked to the development of systemic diseases through various mechanisms. The outer membrane vesicles (OMVs) produced by P. gingivalis play a key role in this process. These OMVs serve as important mediators of communication between bacteria and host cells and other bacteria, carrying and delivering virulence factors to host cells and distant tissues, thereby damaging host cells and exacerbating inflammatory responses. The ability of these OMVs to disseminate and deliver bacterial virulence factors allows P. gingivalis to play a pathogenic role far beyond the confines of the periodontal tissue and has been closely associated with the development of a variety of systemic diseases such as cardiovascular disease, Alzheimer's disease, rheumatoid arthritis, diabetes mellitus, non-alcoholic hepatitis, and cancer. In view of this, it is of great pathophysiological and clinical significance to deeply investigate its pathogenic role and related mechanisms. This will not only help to better understand the pathogenesis of periodontitis and its related systemic diseases but also provide new ideas and more effective and precise strategies for the early diagnosis, prevention, and treatment of these diseases. However, the current research in this field is still insufficient and in-depth, and many key issues and mechanisms need to be further elucidated. This article summarizes the recent research progress on the role of P. gingivalis OMVs (P. g-OMVs) in related diseases, with the aim of providing a theoretical basis and direction for future research and revealing the pathogenic mechanism of P. g-OMVs more comprehensively.},
}

@article {pmid40256246,
year = {2025},
author = {Li, H and Xiao, Q and Zhu, L and Kang, J and Zhan, Q and Peng, W},
title = {Targeting ceramide-induced microglial pyroptosis: Icariin is a promising therapy for Alzheimer's disease.},
journal = {Journal of pharmaceutical analysis},
volume = {15},
number = {4},
pages = {101106},
pmid = {40256246},
issn = {2214-0883},
abstract = {Alzheimer's disease (AD), a progressive dementia, is one of the most common neurodegenerative diseases. Clinical trial results of amyloid-β (Aβ) and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing. There are currently no effective strategies for slowing the progression of AD. Herein, we spotlight the dysregulation of lipid metabolism, particularly the elevation of ceramides (Cers), as a critical yet underexplored facet of AD pathogenesis. Our study delineates the role of Cers in promoting microglial pyroptosis, a form of programmed cell death distinct from apoptosis and necroptosis, characterized by cellular swelling, and membrane rupture mediated by the NLRP3 inflammasome pathway. Utilizing both in vivo experiments with amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice and in vitro assays with BV-2 microglial cells, we investigate the activation of microglial pyroptosis by Cers and its inhibition by icariin (ICA), a flavonoid with known antioxidant and anti-inflammatory properties. Our findings reveal a significant increase in Cers levels and pyroptosis markers (NOD-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, gasdermin D (gasdermin D (GSDMD)), and interleukin-18 (IL-18)) in the brains of AD model mice, indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis. Conversely, ICA treatment effectively reduces these pyroptotic markers and Cer levels, thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD. This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy, capable of mitigating neuroinflammation and pyroptosis through the cyclooxygenase-2 (COX-2)-NLRP3 inflammasome-gasdermin D (GSDMD) axis. Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.},
}

@article {pmid40255124,
year = {2025},
author = {Sheng, X and Du, Z and Gao, Z and Xu, J and Li, L and Shen, G},
title = {An Implantable In-Hydrogel Wireless Supercapacitor-Activated Neuron System Enables Bidirectional Modulation.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e2504558},
doi = {10.1002/adma.202504558},
pmid = {40255124},
issn = {1521-4095},
abstract = {The bidirectional modulation of cerebral neurons in the brain possesses enhancement and inhibition of neural activity, which is of great interest in the treatment of motor nerve disorders and emotional disorders, and cognitive defects. However, existing approaches usually rely on electrical/electrochemical stimulations, which show low security by implanting metal probes and unidirectional currents with single modulation. Herein, an implantable in-hydrogel wireless supercapacitor-activated neuron system consisting of the coil, diode bridge circuit, in-hydrogel supercapacitor, and stimulation electrodes is fabricated, which provides a bidirectional and adjustable ion diffusion current to safely and effectively excite and inhibit brain neurons. The designed in-hydrogel supercapacitor exhibits a high storage charge ability of ≈90 times larger than the devices without hydrogel encapsulation, owing to the in situ radical addition mechanism. Moreover, the in-hydrogel electrodes are implanted into the thalamus, amygdala, and prefrontal lobes of the brain to evoke the corresponding changes in potential intensity and frequency through the external chargeable coil and diode bridge circuit, which verifies the potential of the multimodule supercapacitor in amelioration and treatment Parkinson's, severe depression, and Alzheimer's disease.},
}

@article {pmid40255041,
year = {2025},
author = {Jamal, R and Shaikh, MA and Taleuzzaman, M and Haque, Z and Albratty, M and Alam, MS and Makeen, HA and Zoghebi, K and Saleh, SF},
title = {Key biomarkers in Alzheimer's disease: Insights for diagnosis and treatment strategies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251330500},
doi = {10.1177/13872877251330500},
pmid = {40255041},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) remains a significant global health challenge, characterized by its progressive neurodegeneration and cognitive decline. The urgent need for early diagnosis and effective treatment necessitates the identification of reliable biomarkers that can illuminate the underlying pathophysiology of AD. This review provides a comprehensive overview of the latest advancements in biomarker research, focusing on their applications in diagnosis, prognosis, and therapeutic development. We delve into the multifaceted landscape of AD biomarkers, encompassing molecular, imaging, and fluid-based markers. The integration of these biomarkers, including amyloid-β and tau proteins, neuroimaging modalities, cerebrospinal fluid analysis, and genetic risk factors, offers a more nuanced understanding of AD's complex etiology. By leveraging the power of precision medicine, biomarker-driven approaches can enable personalized treatment strategies and enhance diagnostic accuracy. Moreover, this review highlights the potential of biomarker research to accelerate drug discovery and development. By identifying novel therapeutic targets and monitoring disease progression, biomarkers can facilitate the evaluation of experimental treatments and ultimately improve patient outcomes. In conclusion, this review underscores the critical role of biomarkers in advancing our comprehension of AD and driving the development of effective interventions. By providing a comprehensive overview of the current state-of-the-art, this work aims to inspire future research and contribute to the goal of conquering AD.},
}

@article {pmid40255038,
year = {2025},
author = {Malek, J and Levchenko, A and Robinson, JO and Fong, J and Lin, CR and Jackson, GR and Blumenthal-Barby, J and Shulman, JM and McGuire, AL},
title = {Dilemmas in diagnosing Alzheimer's disease: The peril and promise of self-fulfilling prophecies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251331236},
doi = {10.1177/13872877251331236},
pmid = {40255038},
issn = {1875-8908},
abstract = {To date, there are limited empirical data to inform various approaches to communication with patients receiving information on Alzheimer's disease (AD) risk or diagnosis during the pre-symptomatic or minimally symptomatic stages. This article explores the ethical implications of psychological responses known as self-fulfilling prophecies that may impact cognitive decline among individuals diagnosed with or at risk for AD. We describe questions these potential effects raise about the ways clinicians communicate with patients, as well as how caregivers may interact with patients. Recent advancements in biomarkers and treatment for AD underscore the urgency of understanding these phenomena and developing appropriate responses.},
}

@article {pmid40254895,
year = {2025},
author = {Schworer, EK and Handen, BL and Krinsky-McHale, S and Hom, CL and Clare, ICH and Harp, JP and Pulsifer, MB and Mapstone, M and Head, E and Christian, BT and Hartley, SL and , },
title = {Modified Cued Recall Test: Longitudinal Analysis of Test Versions and Item Recall in Adults With Down Syndrome.},
journal = {Journal of intellectual disability research : JIDR},
volume = {},
number = {},
pages = {},
doi = {10.1111/jir.13237},
pmid = {40254895},
issn = {1365-2788},
support = {UL1 TR001873/TR/NCATS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; U01 AG051406/AG/NIA NIH HHS/United States ; U01 AG051412/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; K99AG084738/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P50 AG16537//National Institutes of Health Programs: The Alzheimers Disease Research Centers Program/ ; P50 AG005133/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; U54 HD090256/HD/NICHD NIH HHS/United States ; U54 HD087011/HD/NICHD NIH HHS/United States ; P50 HD105353/HD/NICHD NIH HHS/United States ; U24 AG21886//National Centralized Repository for Alzheimer Disease and Related Dementias/ ; T32HD007489//Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; //NIHR Applied Research Collaboration East of England/ ; },
abstract = {BACKGROUND: Adults with Down syndrome (DS) have an elevated risk and early age of onset for Alzheimer's disease (AD). To support upcoming clinical AD trials, there is a critical need to establish cognitive outcome measures that can be used to capture intervention effects. One measure that has successfully been used to detect AD-related cognitive decline in the DS population is a measure of episodic memory, the modified Cued Recall Test (mCRT). Demonstrated utility of the mCRT warrants further investigation into comparisons between the A and B versions, free versus cued recall and changes in performance over time to better understand sensitivity for tracking memory decline over time based on age and AD clinical status.

METHOD: Participants were 272 adults with DS aged 25-81 (mean age = 43.12 years, SD = 9.79). Study procedures were completed at three cycles of data collection: baseline, 16-month follow-up and 32-month follow-up. Participants were enrolled in the Alzheimer Biomarker Consortium-Down Syndrome longitudinal study and completed the mCRT as part of a multiday evaluation. Comparisons were made between the A and B versions of the mCRT in recall and intrusion scores. Participants' ratio of free relative to cued recall was also examined at baseline and longitudinally. Participant performance was compared by age group, clinical AD status (cognitively stable [CS], mild cognitive impairment [MCI] or AD dementia) and premorbid level of intellectual disability (ID).

RESULTS: Version differences were identified, with the most salient differences in the moderate and severe/profound ID groups. The mCRT free recall declined with age in CS participants. Free and cued recall scores were lower in those with MCI and AD dementia, with the exception of the mild ID MCI group, whose cued recall scores were not significantly different from the CS group. Decline across 32 months (mCRT total score decline of 1.29 points/year) was observed for CS participants beginning at ≥ 50 years old, with more pronounced declines in adults with DS with an MCI or AD dementia diagnosis (3.36 and 4.20 points/year, respectively).

CONCLUSION: Characterising test version differences and participant free versus cued recall performance on the mCRT is important for understanding performance under testing conditions and to maximise the sensitivity of clinical interventions to capture meaningful effects. Our findings suggest that clinical AD trials for DS should be cautious about using both versions of the mCRT. Examining the profile of free relative to cued recall may enhance sensitivity for detecting treatment benefits for adults with DS across the range of premorbid ID levels.},
}

@article {pmid40254847,
year = {2025},
author = {Song, M and Zhang, S and Gan, Y and Ding, T and Li, Z and Fan, X},
title = {Poria cocos Polysaccharide Reshapes Gut Microbiota to Regulate Short-Chain Fatty Acids and Alleviate Neuroinflammation-Related Cognitive Impairment in Alzheimer's Disease.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c01042},
pmid = {40254847},
issn = {1520-5118},
abstract = {Evidence indicates that Poria cocos polysaccharide (PCP) improves cognitive impairment in Alzheimer's disease (AD); however, its underlying mechanism, particularly its relationship with the gut microbiota, remains unclear. In the current study, we aimed to investigate the mechanism of PCP in improving cognitive impairment in AD. The results demonstrated that PCP markedly enhanced cognitive function and mitigated AD-related pathological alterations in 3 × Tg-AD mice. PCP treatment reversed the age-dependent gut microbiota dysbiosis in 3 × Tg-AD mice by 16S rDNA sequencing. The contents of propanoic acid, butanoic acid and isohexanoic acid were increased by short-chain fatty acid determination. In addition, PCP could restore both the intestinal barrier and the blood-brain barrier, as demonstrated by immunofluorescence staining of tight junction proteins. Furthermore, PCP alleviated systemic inflammation and neuroinflammation, as evidenced by reduced LPS levels in circulation and decreased IL-6 levels in the brain, likely by inhibiting the TLR4/NF-κB signaling pathway. In conclusion, PCP can reshape gut microbiota to regulate short-chain fatty acids and alleviate neuroinflammation-related cognitive impairment in AD mice.},
}

@article {pmid40254603,
year = {2025},
author = {Peralta Ramos, JM and Castellani, G and Kviatcovsky, D and Croese, T and Tsitsou-Kampeli, A and Burgaletto, C and Abellanas, MA and Cahalon, L and Phoebeluc Colaiuta, S and Salame, TM and Kuperman, Y and Savidor, A and Itkin, M and Malitsky, S and Ovadia, S and Ferrera, S and Kalfon, L and Kadmani, S and Samra, N and Paz, R and Rokach, L and Furlan, R and Aharon-Peretz, J and Falik-Zaccai, TC and Schwartz, M},
title = {Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in a mouse model of Alzheimer's disease.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {3736},
pmid = {40254603},
issn = {2041-1723},
mesh = {Animals ; *Alzheimer Disease/immunology/metabolism/drug therapy ; *ADP-ribosyl Cyclase 1/metabolism/immunology/antagonists & inhibitors ; Disease Models, Animal ; Female ; Mice ; Humans ; Mice, Transgenic ; *Cognition/drug effects ; *Membrane Glycoproteins/metabolism/immunology/antagonists & inhibitors ; CD4-Positive T-Lymphocytes/immunology/metabolism ; Th17 Cells/immunology/metabolism/drug effects ; Interleukin-17/metabolism/immunology ; Male ; Interleukin-1beta/metabolism/immunology ; Meninges/immunology ; },
abstract = {Protective immunity, essential for brain maintenance and repair, may be compromised in Alzheimer's disease (AD). Here, using high-dimensional single-cell mass cytometry, we find a unique immunometabolic signature in circulating CD4[+] T cells preceding symptom onset in individuals with familial AD, featured by the elevation of CD38 expression. Using female 5xFAD mice, a mouse model of AD, we show that treatment with an antibody directed to CD38 leads to restored metabolic fitness, improved cognitive performance, and attenuated local neuroinflammation. Comprehensive profiling across distinct immunological niches in 5xFAD mice, reveals a high level of disease-associated CD4[+] T cells that produce IL-17A in the dural meninges, previously linked to cognitive decline. Targeting CD38 leads to abrogation of meningeal TH17 immunity and cortical IL-1β, breaking the negative feedback loop between these two compartments. Taken together, the present findings suggest CD38 as an immunometabolic checkpoint that could be adopted as a pre-symptomatic biomarker for early diagnosis of AD, and might also be therapeutically targeted alone or in combination with other immunotherapies for disease modification.},
}

Animals
*Alzheimer Disease/immunology/metabolism/drug therapy
*ADP-ribosyl Cyclase 1/metabolism/immunology/antagonists & inhibitors
Disease Models, Animal
Female
Mice
Humans
Mice, Transgenic
*Cognition/drug effects
*Membrane Glycoproteins/metabolism/immunology/antagonists & inhibitors
CD4-Positive T-Lymphocytes/immunology/metabolism
Th17 Cells/immunology/metabolism/drug effects
Interleukin-17/metabolism/immunology
Male
Interleukin-1beta/metabolism/immunology
Meninges/immunology

@article {pmid40254404,
year = {2025},
author = {Muraleva, NA and Zhdankina, AA and Khlebnikov, AI and Kolosova, NG},
title = {JNK Signaling Pathway Activity Alterations in the Rat Hippocampus: Effect of Age, Alzheimer's Disease-Like Pathology Development, and the JNK Inhibitor IQ-1S.},
journal = {Biochemistry. Biokhimiia},
volume = {90},
number = {2},
pages = {265-275},
doi = {10.1134/S0006297924603903},
pmid = {40254404},
issn = {1608-3040},
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Hippocampus/metabolism/pathology/drug effects ; Rats ; Rats, Wistar ; *MAP Kinase Signaling System/drug effects ; Male ; *Aging/metabolism ; *Protein Kinase Inhibitors/pharmacology ; Mitogen-Activated Protein Kinase 10/metabolism/antagonists & inhibitors ; Phosphorylation ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of senile dementia. The key risk factor for a more common (>95% of cases) sporadic form of AD is age. So far, there are no effective methods for AD prevention or treatment. A growing body of evidence indicates that the development of AD and other neurodegenerative diseases is associated with the activation of mitogen-activated protein kinase (MAPK) pathways, and JNK signaling pathway is considered as a potential target for the prevention and treatment of AD. However, the information on alterations in its activity in ontogenesis, which are evaluated by changes in the phosphorylation of its components, is extremely limited. The aim of this study was to compare age-related changes in the activity of JNK signaling pathway in the hippocampus of Wistar rats and senescence-accelerated OXYS rats (which spontaneously develop the key symptoms of AD-like pathology) and to evaluate the effect of the selective JNK3 inhibitor IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt). The ability of IQ-1S to suppress accelerated brain aging in OXYS rat has been proven previously, but the effect of this inhibitor on the JNK activity has not been studied. Here, we showed that with age, the activity of the JNK signaling pathway increased in the hippocampus of rats of both strains. At the same time, the manifestation and active progression of AD-like pathology in OXYS rats was accompanied by the increase in the phosphorylation level of the key kinase of this signaling pathway, JNK3, and its target proteins compared to Wistar rats, which allowed us to suggest JNK3 as a potential target for interventions aimed at preventing neurodegenerative processes. This suggestion was supported by the fact that the neuroprotective effect of the selective JNK3 inhibitor IQ-1S and its ability to suppress the development of neurodegenerative processes in OXYS rats were associated with a decrease in the phosphorylation levels of JNK3, c-Jun, APP, and Tau in the hippocampus.},
}

Animals
*Alzheimer Disease/metabolism/pathology/drug therapy
*Hippocampus/metabolism/pathology/drug effects
Rats
Rats, Wistar
*MAP Kinase Signaling System/drug effects
Male
*Aging/metabolism
*Protein Kinase Inhibitors/pharmacology
Mitogen-Activated Protein Kinase 10/metabolism/antagonists & inhibitors
Phosphorylation

@article {pmid40253707,
year = {2025},
author = {Fredriksen-Goldsen, KI and Kim, HJ and Teri, L and Jones-Cobb, BR and Fazia, D and Petros, R and Berridge, C and Prasad, A and Oswald, A and Emlet, CA},
title = {Older adults living with Alzheimer's Disease, dementia or mild cognitive impairment with no informal caregiver or care partner: IDEA Café, the first pilot randomized trial intervention for this underserved populations.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/13607863.2025.2468893},
pmid = {40253707},
issn = {1364-6915},
abstract = {OBJECTIVES: This study presents findings from IDEA Café, for older adults aged 50 and older living with early dementia, dementia, Alzheimer's Disease or cognitive impairment (ED/CI) with no informal caregiver or care partner. IDEA Café is a group adaptation of Innovations in Dementia Empowerment and Action (IDEA) (built upon the foundation of RDAD). It was tested with sexual and gender minority (SGM) older adults, as an underserved population.

METHOD: Employing a two-group randomized controlled pilot trial, thirty participants were randomly assigned to IDEA Café (n = 15) or routine medical care (RMC; n = 15). Feasibility and acceptability were assessed. We conducted pre- and post-treatment assessments of primary and secondary outcomes.

RESULTS: IDEA Café was feasible (attendance, participation), acceptable (helpfulness of the program), and met enrollment goals, with 85% of participants reporting treatment as helpful. The treatment group showed significant improvement in physical functioning (p = 0.04), depressive symptomology (p = 0.03), quality of life (p = 0.04), and a reduction in microaggressions (p = 0.05) and social exclusion (p = 0.03). The RMC showed no statistical change from pretest to posttest.

CONCLUSION: A future randomized controlled trial is needed to test the efficacy and sustainability of the intervention and to bring the intervention to scale.},
}

@article {pmid40253583,
year = {2025},
author = {El-Molla, AM and Aboul Fetouh, F and Bawazir, S and Alwahby, YA and Ali, YA and Basseet, AA and Albanna, AH},
title = {Epinephrine as a Therapeutic Agent for Hyperferritinemia in Diabetes Mellitus and Hypertension.},
journal = {The American journal of case reports},
volume = {26},
number = {},
pages = {e947289},
doi = {10.12659/AJCR.947289},
pmid = {40253583},
issn = {1941-5923},
mesh = {Humans ; *Diabetes Mellitus, Type 2/complications/drug therapy ; *Epinephrine/therapeutic use ; *Hypertension/complications/drug therapy ; *Hyperferritinemia/drug therapy/etiology ; Male ; Middle Aged ; Ferritins/blood ; COVID-19 ; },
abstract = {BACKGROUND Diabetes mellitus was the first non-communicable disease to be recognized as a 21st century pandemic. Type 2 diabetes (T2DM) results from increased insulin resistance (IR) or relative insulin deficiency. IR impairs glucose disposal, leading to a compensatory hyper-insulinemic state. Increased iron stores as reflected by high serum ferritin (SF) have been associated with the development T2DM and affect glucose homeostasis by impairing tissue response to insulin. Iron overload (IO) is quite common in essential hypertension (HTN). The first clinical effect of epinephrine on SF was reported in 2024, showing that epinephrine resulted in normalization of SF and recovery from severe COVID-19 infection. CASE REPORT A patient with T2DM, HTN, and dyslipidemia associated with hyperferritinemia received the conventional treatment of T2DM and HTN, with a poor control of hyperglycemia and HTN. Since the patient had elevated SF, we obtained informed written consent for epinephrine's use to lower SF. Epinephrine 0.6 mcg/kg was injected subcutaneously under hemodynamic monitoring, and the results showed normalization of SF and complete recovery of T2DM and HTN. CONCLUSIONS Epinephrine can normalize elevated SF by its iron chelating effect; therefore, it can relieve IO and alleviate IR associated with T2DM and HTN. Epinephrine has an anti-inflammatory and scavenging properties that can inhibit ferroptosis. As a new clinical indication, extensive studies are required for further assessment and possible therapeutic uses in IO disorders such as hereditary hemochromatosis (HH), Alzheimer disease (AD), Parkinsonian disease (PD), and multiple sclerosis (MS).},
}

Humans
*Diabetes Mellitus, Type 2/complications/drug therapy
*Epinephrine/therapeutic use
*Hypertension/complications/drug therapy
*Hyperferritinemia/drug therapy/etiology
Male
Middle Aged
Ferritins/blood
COVID-19

@article {pmid40253440,
year = {2025},
author = {Khan, S and Choudhury, A and Mohammad, T and Shamsi, A and Hassan, MI and Islam, A},
title = {Structure-guided screening identified bioactive phytoconstituents Hernandonine and Anolobine as potential inhibitors of dual specificity protein kinase CLK1.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {13604},
pmid = {40253440},
issn = {2045-2322},
mesh = {*Protein Serine-Threonine Kinases/antagonists & inhibitors/chemistry/metabolism ; Molecular Docking Simulation ; *Protein Kinase Inhibitors/chemistry/pharmacology ; *Protein-Tyrosine Kinases/antagonists & inhibitors/chemistry/metabolism ; Humans ; *Phytochemicals/chemistry/pharmacology ; Molecular Dynamics Simulation ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD) are becoming a global health concern because of their progressive nature and the extent of the disability they cause to the affected individuals. Existing therapies for neurodegenerative diseases are primarily limited to symptomatic management and have shown diminishing efficacy over time, often leading to resistance. Therefore, there is an urgent need for novel therapeutic interventions that offer improved effectiveness with fewer side effects. A promising approach that has been suggested in neurodegenerative diseases, especially AD, is the prevention of tau phosphorylation by using kinase inhibitors. CDC2-like kinase 1 (CLK1) is a dual-specificity proline-directed protein kinase that is involved in both tau phosphorylation and splicing regulation and is thus a potential drug target. Currently, there are several small molecular CLK1 inhibitors, but problems like drug resistance and side effects still exist. In this study, we have used a structure-guided virtual screening approach to screen the bioactive phytoconstituents of Indian medicinal plants for potential CLK1 inhibitors. The systematic virtual screening involving molecular docking, density functional theory (DFT), and pharmacokinetic profiling, pinpointed Hernandonine and Anolobine as promising compounds due to their druglike properties and high binding affinity with CLK1. To assess the stability and interaction of these compounds with CLK1, all-atom molecular dynamics (MD) simulations and essential dynamics were performed for 500 ns. The results indicate that Hernandonine and Anolobine have a high potential for CLK1 inhibition and can be used as promising leads for developing novel effective drugs against neurodegeneration. This work underlines the importance of the combined use of virtual screening and MD simulations in the search for phytochemical-based CLK1 inhibitors, which can lead to the development of new therapeutic approaches in the treatment of neurodegenerative diseases such as AD.},
}

*Protein Serine-Threonine Kinases/antagonists & inhibitors/chemistry/metabolism
Molecular Docking Simulation
*Protein Kinase Inhibitors/chemistry/pharmacology
*Protein-Tyrosine Kinases/antagonists & inhibitors/chemistry/metabolism
Humans
*Phytochemicals/chemistry/pharmacology
Molecular Dynamics Simulation

@article {pmid40253240,
year = {2025},
author = {Angioni, D and Middleton, L and Bateman, R and Aisen, P and Boxer, A and Sha, S and Zhou, J and Gerlach, I and Raman, R and Fillit, H and Salloway, S and Sperling, R and Vellas, B and Cummings, J},
title = {Challenges and opportunities for novel combination therapies in Alzheimer's disease: a report from the EU/US CTAD Task Force.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100163},
doi = {10.1016/j.tjpad.2025.100163},
pmid = {40253240},
issn = {2426-0266},
abstract = {Following the recent approvals of anti-amyloid immunotherapies as "first-in-kind" disease-modifying agents for Alzheimer's disease (AD), there is an emerging emphasis in combination therapies, given the complex and multifactorial etiopathogenesis and pathophysiology of the disease. The EU/US CTAD Task Force met in Madrid in October 2024, to discuss biological rationale and methodological issues and outline potential directions for future research in combination therapies. The Task Force agreed on the necessity and urgency of advancing combination therapies for AD treatment. As of January 1, 2024, in the drug development pipeline, there were 21 combination trials (13 % of all trials). The combination of anti-amyloid and anti-tau therapies could become a central focus of the field. Combinations involving anti-inflammatory and immune mechanisms with anti-amyloid or other therapies also have promise. To facilitate the development and implementation of combination therapies, collaborations between sponsors and public-private partnerships are essential. Optimizing the likelihood of success primarily requires leveraging the use of biomarkers and a clearer understanding of the biological mechanisms underpinning AD and their interactions, especially those involving amyloid, tau, and inflammation, that lead to cognitive decline and progression.},
}

@article {pmid40253039,
year = {2025},
author = {Malaiya, A and Kenwat, R and Mamgain, A and Nayak, P and Parker, A and Paliwal, SR and Paliwal, R},
title = {Intranasal resveratrol delivery to the brain with chitosan-decorated bovine serum albumin nanoparticles: Advancing Alzheimer's management in old female rats through QbD-based optimization, in vitro evaluation, and in vivo exploration.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {143300},
doi = {10.1016/j.ijbiomac.2025.143300},
pmid = {40253039},
issn = {1879-0003},
abstract = {This study aims to prepare, characterize, and evaluate the potential of chitosan-coated bovine serum albumin nanoparticles (CS-BSANPs) loaded with resveratrol (RES) to enhance the therapeutic properties of RES and target Alzheimer's disease in elderly females. As confirmed by morphological analysis, the BSANPs were synthesized using desolvation techniques, resulting in spherical and smooth nanoparticles. Both RES-BSANPs and CS-RES-BSANPs exhibited stability for 90 days at ambient refrigerated temperatures. Through optimization using a Box-Behnken design, RES-BSANPs with favorable colloidal properties were achieved. Differential scanning calorimetry and powder X-ray diffraction confirmed the amorphous dispersion of RES within the nanocarriers. In vitro drug release studies demonstrated a biphasic release pattern aligned with the Korsmeyer-Peppas model, exhibiting both burst and sustained release phases. Stability tests indicated that RES-BSA-NPs and CS-RES-NPs remain stable at 4 °C. Ex vivo studies verified the safety of RES-loaded nanoparticles, and behavioral tests on the Wistar rat model showed that intranasally administered CS-RES-BSANPs were more effective than plain RES dispersion. These results emphasize the potential of biodegradable and mucoadhesive CS-RES-BSANPs as effective drug carriers for intranasal delivery to the brain, offering safety and high tolerability for Alzheimer's disease treatment.},
}

@article {pmid40252967,
year = {2025},
author = {Aghamoosa, S and Nolin, SA and Chen, A and Caulfield, KA and Lopez, J and Rbeiz, K and Fleischmann, HH and Horn, O and Madden, K and Antonucci, M and Revuelta, G and McTeague, LM and Benitez, A},
title = {Accelerated iTBS-Induced Changes in Resting-State Functional Connectivity Correspond with Cognitive Improvement in Amnestic MCI.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.brs.2025.04.012},
pmid = {40252967},
issn = {1876-4754},
abstract = {BACKGROUND: Published results of our Phase I safety and feasibility trial of accelerated intermittent theta burst stimulation (a-iTBS) in mild cognitive impairment (MCI) due to Alzheimer's disease showed a large effect-size improvement in cognition.

OBJECTIVE: Further demonstrate target engagement by identifying whether changes in local and network-level functional connectivity relate to the observed cognitive improvement.

METHODS: Eighteen patients with MCI received 3-day a-iTBS (8 sessions/day) to the left dorsolateral prefrontal cortex at Beam F3 (14,400 total pulses) and completed MRI and cognitive testing at pre- and post-treatment. Based on electric field models, we selected 3 stimulated target regions of interest (ROIs) which belonged to the frontoparietal (FPN), default mode (DMN), and ventral attention (VAT) networks (3 target networks). Metrics of resting-state functional connectivity were computed at the ROI level (within-network degree: number of connections) and network level (segregation: strength of connectivity within network relative to other networks). We correlated changes in cognition and connectivity for the target ROIs and networks; off-target ROI (primary visual) and networks serve as negative controls.

RESULTS: Improvements in cognition were associated with connectivity changes in the target ROIs and networks, but not in off-target negative controls. Positive associations were observed for degree of the l-DMN and segregation of target networks overall, with significant effects for DMN and VAT.

CONCLUSION: Cognitive improvement following a-iTBS in MCI may be attributable to local and network-level reconfigurations in functional connectivity. These findings will inform larger trials designed to further evaluate the neural mechanisms of a-iTBS for cognition in MCI.},
}

@article {pmid40252920,
year = {2025},
author = {Vigil Díaz, C and Paredes Rodríguez, P and Perissinotti, A and Fernando Guillén, E and López Mora, D and Lojo Ramírez, JA and Aguiar Fernández, P and Camacho Martí, MV and Nieves Cabrera-Martín, M and , },
title = {Procedure update and interpretation guide for the brain [18]F-FDG PET study.},
journal = {Revista espanola de medicina nuclear e imagen molecular},
volume = {},
number = {},
pages = {500159},
doi = {10.1016/j.remnie.2025.500159},
pmid = {40252920},
issn = {2253-8089},
abstract = {The increase in the prevalence of dementia in our clinical setting poses a diagnostic challenge for the Nuclear Medicine specialist. The aim of this study is to review the modifications in the procedure and to describe the usefulness of the use of brain PET with [18]F-FDG in different clinical indications, both classic and emerging ones. The SEMNIM Neuroimaging working group has considered it appropriate to update the procedures available in Spanish, in order to optimize the quality of this technique and the interpretation of its findings, both for the specialist in Nuclear Medicine and the rest of the professionals involved in the diagnosis and treatment of neurodegenerative diseases.},
}

@article {pmid40252828,
year = {2025},
author = {Zhao, Y and Zhao, W and Chai, X and Sun, P and Huang, J and Guo, X and Zhang, L and Ren, D and Yi, C and Zhu, X and Zhao, S},
title = {Reshaping the gut microbiota: A novel oppinion of Eucommiae cortex polysaccharide alleviate learning and memory impairments in Alzheimer's disease.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2025.04.025},
pmid = {40252828},
issn = {2090-1224},
abstract = {BACKGROUND: Alzheimer's disease (AD), which is a chronic neurodegenerative disorder, is marked by the progressive deteriorations in learning and memory capabilities. The microbiota-gut-brain axis has come to be regarded as a crucial element in relation to the pathogenesis as well as the treatment of AD. Eucommiae cortex polysaccharides (EPs), being among the most plentiful substances present in the Eucommiae cortex, show the potential to exert immunomodulatory and neuroprotective function. However, whether EPs are protective against AD and their mechanism of action remain to be investigated OBJECTIVES: We hypothesize that EPs can regulate brain glutamine metabolism through gut microbiota and the butyric acid metabolized by them, improve oxidative stress and autophagy in the brain, and thus alleviate AD.

METHODS: In the present study, we used EPs (0.25 % w/w in food) and fecal microbiota transplantation, as well as butyrate supplementation (0.1 M in water), to intervene in AD mice. Multi-omics were used to determine the mechanism by which EPs improve AD-related learning and memory impairments.

RESULTS: Our results suggest that EPs, functioning as a prebiotic, alleviated learning and memory impairments in AD mice. Mechanistically, EPs are able to reshape the gut microbiota, promote the growth of gut microbiota involved in short-chain fatty acid metabolism, particularly butyrate-producing microbes. The butyrate produced by these microbes improves the brain microenvironment by modulating oxidative stress and autophagy mediated by brain glutamate metabolism, improving learning and memory impairments in AD mice, and inhibiting the formation and deposition of beta-amyloid proteins. Fecal microbiota transplantation (FMT) and butyrate supplementation further confirm this conclusion.

CONCLUSIONS: Our results highlighted that EPs can alleviate learning and memory impairments in AD with a gut microbiota-dependent manner and that butyric acid metabolized by butyric acid-metabolizing bacteria in the gut plays a central role in regulating brain glutamine metabolism to improve brain microenvironmental homeostasis. Meanwhile, the present study provides new insights into the treatment of AD with natural products.},
}

@article {pmid40251832,
year = {2025},
author = {Bresque, M and Esteve, D and Balmer, G and Hamilton, HL and Stephany, JS and Pehar, M and Vargas, MR},
title = {FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.},
journal = {Glia},
volume = {},
number = {},
pages = {},
doi = {10.1002/glia.70023},
pmid = {40251832},
issn = {1098-1136},
support = {R01NS122973/NH/NIH HHS/United States ; R01NS132760/NH/NIH HHS/United States ; },
abstract = {Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.},
}

@article {pmid40251199,
year = {2025},
author = {Sangeet, S and Khan, A},
title = {Bacopa monnieri phytochemicals as promising BACE1 inhibitors for Alzheimer's disease therapy.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {13504},
pmid = {40251199},
issn = {2045-2322},
mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors/chemistry/metabolism ; *Alzheimer Disease/drug therapy ; *Bacopa/chemistry ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism/chemistry ; Molecular Docking Simulation ; Humans ; *Phytochemicals/pharmacology/chemistry/therapeutic use ; Protein Binding ; Triterpenes/chemistry/pharmacology ; },
abstract = {Alzheimer's disease (AD) remains a formidable challenge, necessitating the discovery of effective therapeutic agents targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1). This study investigates the inhibitory potential of phytochemicals derived from Bacopa monnieri, a plant renowned for its cognitive-enhancing properties, in comparison to established synthetic inhibitors such as Atabecestat, Lanabecestat, and Verubecestat. Utilizing molecular docking and advanced computational simulations, we demonstrate that Bacopaside I exhibits superior binding affinity and a unique interaction profile with BACE1, suggesting a more nuanced inhibitory mechanism. Our findings highlight the promising role of Bacopa monnieri phytochemicals as viable alternatives to synthetic drugs, emphasizing their potential to overcome limitations faced in clinical settings. Furthermore, the development of the SIMANA (https://simana.streamlit.app/) platform enhances the visualization and analysis of protein-ligand interactions, facilitating a deeper understanding of the dynamics involved. This research not only underscores the therapeutic promise of natural compounds in AD treatment but also advocates for a paradigm shift towards integrating traditional medicinal knowledge into contemporary drug discovery efforts.},
}

*Amyloid Precursor Protein Secretases/antagonists & inhibitors/chemistry/metabolism
*Alzheimer Disease/drug therapy
*Bacopa/chemistry
*Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism/chemistry
Molecular Docking Simulation
Humans
*Phytochemicals/pharmacology/chemistry/therapeutic use
Protein Binding
Triterpenes/chemistry/pharmacology

@article {pmid40250750,
year = {2025},
author = {Noda, K and Kageyama, I and Kobayashi, Y and Lim, Y and Sengoku, S and Kodama, K},
title = {Leveraging mHealth wearables for managing patients with Alzheimer's disease: a scoping review.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104363},
doi = {10.1016/j.drudis.2025.104363},
pmid = {40250750},
issn = {1878-5832},
abstract = {In this scoping review, we examine the role of wearable devices in diagnosing, treating, and monitoring Alzheimer's disease (AD) and mild cognitive impairment (MCI). It identifies various devices, including fitness trackers, smartwatches, electroencephalographic equipment, and sensors, which are used for monitoring physical activity, sleep patterns, and cognitive functions. Our review highlights the potential of these devices for early diagnosis and treatment, improving patient autonomy and quality of life. However, challenges, such as data privacy, device adherence, and technical limitations, remain. Future research should focus on integrating wearable devices with advanced diagnostic tools and validating their effectiveness across diverse populations.},
}

@article {pmid40250748,
year = {2025},
author = {Ahsan, R and Khan, MM and Mishra, A and Noor, G and Ahmad, U},
title = {Plumbagin as a potential therapeutic agent for scopolamine-induced Alzheimer's disease: Mechanistic insights into GSK-3β inhibition.},
journal = {Brain research},
volume = {},
number = {},
pages = {149650},
doi = {10.1016/j.brainres.2025.149650},
pmid = {40250748},
issn = {1872-6240},
abstract = {BACKGROUND: The study aimed to evaluate Plumbagin's neuroprotective potential against scopolamine-induced Alzheimer's disease, proposing that its effects may involve GSK-3β inhibition, a key factor in tau hyperphosphorylation, to promote neuroprotection in Wistar rats.

METHODS: Alzheimer's was induced in male Wistar rats. After acclimatization, the rats were subjected to daily intraperitoneal treatment with scopolamine (0.7 mg/kg) and oral administration of Plumbagin (10 mg/kg) for 13 days. The cognitive function of treated rats was evaluated using the Morris water maze test, along with assessments of locomotor activity, acetylcholinesterase activity (AChE), protein levels, antioxidant parameters, cytokines and Brain-Derived Neurotrophic Factor (BDNF) and brain histopathology (hippocampus).

RESULTS: The Plumbagin (10 mg/kg, oral) as given orally significantly improved neurobehavioral alterations compared to Alzheimer's induced group. Scopolamine impaired cognitive function and increased locomotor activity ([#]P < 0.05). Treatments improved Morris water maze performance, reducing Escape latency time and increasing Time spent in the target quadrant (*P < 0.05). Biochemically, treatments significantly improved BDNF (*P < 0.05), decreased AChE activity, oxidative stress, reduced Interleukin-6 and Tumor Necrosis Factor Alpha (*P < 0.05) and reversed Scopolamine induced hippocampal neuronal loss ([##]P < 0.01). Plumbagin showed significant (*P < 0.05) neuroprotective effects, improving cognitive function, reducing AChE activity, Malondialdehyde, oxidative stress, and neuroinflammatory markers exceeding individual treatments in the scopolamine-induced Alzheimer's disease model. These improvements suggest a possible mechanism through the inhibition of GSK-3β, which may contribute to the observed neuroprotective effects.

CONCLUSION: This study suggests that Plumbagin's neuroprotective effects in scopolamine-induced Alzheimer's disease may involve GSK-3β inhibition. Plumbagin shows significant therapeutic potential for Alzheimer's treatment, warranting further investigation of its mechanism.},
}

@article {pmid40249069,
year = {2025},
author = {Behera, P and Mishra, M},
title = {Lipid Droplet in Lipodystrophy and Neurodegeneration.},
journal = {Biology of the cell},
volume = {117},
number = {4},
pages = {e70009},
doi = {10.1111/boc.70009},
pmid = {40249069},
issn = {1768-322X},
support = {221610052028//UGC/ ; },
mesh = {Humans ; *Lipodystrophy/metabolism/pathology ; *Lipid Droplets/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Lipid Metabolism ; },
abstract = {Lipid droplets are ubiquitous yet distinct intracellular organelles that are gaining attention for their uses outside of energy storage. Their formation, role in the physiological function, and the onset of the pathology have been gaining attention recently. Their structure, synthesis, and turnover play dynamic roles in both lipodystrophy and neurodegeneration. Factors like development, aging, inflammation, and cellular stress regulate the synthesis of lipid droplets. The biogenesis of lipid droplets has a critical role in reducing cellular stress. Lipid droplets, in response to stress, sequester hazardous lipids into their neutral lipid core, preserving energy and redox balance while guarding against lipotoxicity. Thus, the maintenance of lipid droplet homeostasis in adipose tissue, CNS, and other body tissues is essential for maintaining organismal health. Insulin resistance, hypertriglyceridemia, and lipid droplet accumulation are the severe metabolic abnormalities that accompany lipodystrophy-related fat deficit. Accumulation of lipid droplets is detected in almost all neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and Hereditary spastic paraplegia. Hence, the regulation of lipid droplets can be used as an alternative approach to the treatment of several diseases. The current review summarizes the structure, composition, biogenesis, and turnover of lipid droplets, with an emphasis on the factors responsible for the accumulation and importance of lipid droplets in lipodystrophy and neurodegenerative disease.},
}

Humans
*Lipodystrophy/metabolism/pathology
*Lipid Droplets/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
Animals
Lipid Metabolism

@article {pmid40248597,
year = {2025},
author = {Guo, Z and Jiang, Y and He, J and Jiang, N},
title = {Repetitive transcranial magnetic stimulation may promote the reversion of mild cognitive impairment to normal cognition.},
journal = {Frontiers in psychiatry},
volume = {16},
number = {},
pages = {1544728},
pmid = {40248597},
issn = {1664-0640},
abstract = {PURPOSE: This study aimed to investigate the potential effects of repetitive transcranial magnetic stimulation (rTMS) on the reversion of mild cognitive impairment (MCI) to normal cognitive function and to elucidate the underlying mechanisms.

METHODS: The study enrolled 25 MCI participants, who underwent a 10-day of rTMS treatment and an 18-month follow-up, along with 15 healthy subjects. Participants with MCI were categorized into MCI reverters (MCI-R) and MCI maintainers (MCI-M). We assessed differences in baseline cognitive performance, functional connectivity, and changes of cognitive functions after rTMS between MCI-R and MCI-M to identify possible predictors of reversion of MCI and explore the neural modulation mechanisms.

RESULTS: MCI-M exhibited more severe cognitive impairments across more domains, particularly in language function (p < 0.05). Functional connectivity was more severely damaged in MCI-M participants, notably within the default mode network (DMN), executive control network (ECN), and frontoparietal network (FPN). After rTMS therapy, MCI-R participants demonstrated more significantly improved immediate and delayed recall memory scores (p < 0.05). These memory function changes and baseline functional connectivity of DMN, ECN, and FPN were predictive of the reversion of MCI.

CONCLUSIONS: The efficacy of rTMS in memory function may promote the reversion of MCI to normal cognition, with the functional connectivity of DMN, ECN, and FPN playing a crucial important role. The severity of cognitive impairment and functional connectivity damage correlated with the likelihood of the reversion of MCI to normal cognition, underscoring the importance of early rTMS intervention for dementia prevention.},
}

@article {pmid40248168,
year = {2024},
author = {Park, J and Lee, C and Lin, L and Galvin, J and Fain, MJ and Allen, A and Park, L and Ahn, H},
title = {Efficacy of Home-Based Remotely Supervised Transcranial Direct Current Stimulation for Managing Neuropsychiatric Symptoms in Older Adults With Alzheimer's Disease and Related Dementias.},
journal = {Integrative and complementary therapies},
volume = {30},
number = {5},
pages = {209-219},
pmid = {40248168},
issn = {2768-3206},
abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent among persons with Alzheimer's disease and related dementias (ADRD). However, there are limited safe and effective nonpharmacological treatments for controlling NPS. Transcranial direct current stimulation (tDCS) is a promising noninvasive and safe treatment.

MATERIALS AND METHODS: This study investigated the effects of remotely supervised tDCS in managing NPS in older adults with mild to moderate ADRD. Forty older adults diagnosed with early-stage ADRD were randomly assigned in a 1:1 ratio to receive home-based active tDCS (n = 20) or sham tDCS (n = 20).

RESULTS: Results showed a significantly greater improvement in the following NPS: scratching (P = 0.052, Hedges' g = -0.60 [confidence interval {CI}:
-1.24, 0.04], Cliff's δ = -0.41 [CI: -0.67, -0.06]), nighttime behaviors (P = 0.041; Hedges' g = -0.62 [CI: -1.26, 0.03]; Cliff's δ = -0.41 [CI: -0.67, -0.06], and appetite/eating changes (P = 0.010; Hedges' g = -0.78 [CI: -1.43, -0.13]; Cliff's δ = -0.41 [CI: - 0.56, -0.10]).

CONCLUSION: This study shows promising initial results for using home-based, remotely supervised tDCS to manage NPS, such as nighttime behaviors, changes in eating and appetite, and scratching. Larger studies with more participants are needed to explore various tDCS doses and their long-term effects on NPS.},
}

@article {pmid40248108,
year = {2025},
author = {Lee, S and Liu, R and Cheng, F and Zhang, P},
title = {A Deep Subgrouping Framework for Precision Drug Repurposing via Emulating Clinical Trials on Real-world Patient Data.},
journal = {KDD : proceedings. International Conference on Knowledge Discovery & Data Mining},
volume = {2025},
number = {v1},
pages = {2347-2358},
pmid = {40248108},
issn = {2154-817X},
abstract = {Drug repurposing identifies new therapeutic uses for existing drugs, reducing the time and costs compared to traditional de novo drug discovery. Most existing drug repurposing studies using real-world patient data often treat the entire population as homogeneous, ignoring the heterogeneity of treatment responses across patient subgroups. This approach may overlook promising drugs that benefit specific subgroups but lack notable treatment effects across the entire population, potentially limiting the number of repurposable candidates identified. To address this, we introduce STEDR, a novel drug repurposing framework that integrates subgroup analysis with treatment effect estimation. Our approach first identifies repurposing candidates by emulating multiple clinical trials on real-world patient data and then characterizes patient subgroups by learning subgroup-specific treatment effects. We deploy STEDR to Alzheimer's Disease (AD), a condition with few approved drugs and known heterogeneity in treatment responses. We emulate trials for over one thousand medications on a large-scale real-world database covering over 8 million patients, identifying 14 drug candidates with beneficial effects to AD in characterized subgroups. Experiments demonstrate STEDR's superior capability in identifying repurposing candidates compared to existing approaches. Additionally, our method can characterize clinically relevant patient subgroups associated with important AD-related risk factors, paving the way for precision drug repurposing.},
}

@article {pmid40248097,
year = {2025},
author = {Jia, J and Zhao, S and Zhao, J and Gao, Y},
title = {Engineered nanoparticles for the treatment of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1510798},
pmid = {40248097},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is one of the most common diseases characterized by neurodegeneration and is becoming a major public health problem worldwide. AD is manifested mainly by progressive impairments in cognition, emotion, language and memory in the elderly population. Many treatment strategies have been explored for decades; however, there is still no effective way to address the root cause of AD pathogenesis, only to target symptoms to improve patient cognitive outcomes. Intracerebral administration is difficult because of the challenges posed by the blood‒brain barrier (BBB). NPs are materials with sizes between 1 and 100 nm that can improve biocompatibility, extend the half-life, transport macromolecules, be delivered across the BBB to the central nervous system, and exhibit good targeting capabilities. NPs can provide new ideas for the treatment of AD in terms of their antiaging, antineuroinflammatory, antioxidative, and nerve repair-promoting effects. In this manuscript, we first describe the relationship between AD and the BBB. Second, we introduce the application of nanoparticles for AD treatment. Finally, we summarize the challenges faced by nanoparticles in the treatment of AD.},
}

@article {pmid40247766,
year = {2025},
author = {Randhawa, S and Saini, TC and Bathla, M and Teji, N and Acharya, A},
title = {Biofilm Biology to Brain Health: Harnessing Microbial Wisdom to Uncover Amyloid Dissociating Bifunctional Nano Chaperones for Alzheimer's Therapeutics.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.4c00868},
pmid = {40247766},
issn = {1948-7193},
abstract = {Microbial infections have long been implicated in the gut-brain link to Alzheimer's disease (AD). These infections may influence AD development either directly, through brain invasion, or indirectly via bacterial metabolites crossing the blood-brain-barrier (BBB) or interacting with the enteric nervous system (ENS). Such findings have inspired clinicians to repurpose antimicrobial drugs for AD, yielding promising results. However, the sole bacterial link to AD may be insufficiently understood. Bacterial amyloid presence in biofilms is well-documented, with certain bacterial proteins exacerbating amyloid formation while others inhibit it. For instance, Curli-specific gene protein C (CsgC) in E. coli suppresses curli amyloid formation. This review investigates the possibility of human CsgC-like proteins, identifying beta-2 microglobulin (β2M) and E3 ubiquitin ligases (E3s) as potential analogs that may influence amyloid degradation. We propose that nanoparticles (NPs) could serve as platforms to anchor these proteins, forming Amyloid Dissociating Bifunctional NanoChaperones (ADBiNaCs) with enhanced antiamyloidogenic activity. This innovative approach holds promise for novel AD treatment strategies, meriting further investigation into the role of bacterial and human amyloid-modulating proteins in AD pathology.},
}

@article {pmid40247604,
year = {2025},
author = {Rahman, SM and Tan, C and Kakita, A and Moruno-Manchon, JF},
title = {Sex differences in brain iron deposition and microglial ferritin in Alzheimer's disease.},
journal = {Science progress},
volume = {108},
number = {2},
pages = {368504251336080},
doi = {10.1177/00368504251336080},
pmid = {40247604},
issn = {2047-7163},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Microglia/metabolism/pathology ; Female ; Male ; *Iron/metabolism ; *Brain/metabolism/pathology ; Aged ; *Ferritins/metabolism ; *Sex Characteristics ; Aged, 80 and over ; Apoferritins/metabolism ; Sex Factors ; },
abstract = {ObjectiveIron is the most abundant metal in the human brain, and plays a crucial role in many biological processes. However, disruptions in brain iron metabolism can lead to iron buildup, which occurs with aging and is linked to several brain disorders, including Alzheimer's disease. Microglia, the brain's resident immune cells, have the highest capacity to store iron, which is stored intracellularly within ferritin complexes. Importantly, women are at a higher risk of developing Alzheimer's disease and experience faster disease progression compared to men.MethodsWe used postmortem brain samples from patients with Alzheimer's disease and small vessel disease patients of both sexes for immunohistochemical studies. Samples were stained with the Prussian blue method to visualize iron deposits and with antibodies against the microglia marker Iba1 and ferritin light chain.ResultsOur study reveals that the number of iron deposits and the levels of ferritin light chain in microglia are positively correlated in men with Alzheimer's disease, but negatively correlated in women. There is no correlation between brain iron deposition and ferritin in samples from patients with small vessel disease of both sexes.ConclusionsThese results could inform more tailored approaches to the treatment and management of Alzheimer's disease based on sex-specific differences in brain iron metabolism and microglial iron storage capacity.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Microglia/metabolism/pathology
Female
Male
*Iron/metabolism
*Brain/metabolism/pathology
Aged
*Ferritins/metabolism
*Sex Characteristics
Aged, 80 and over
Apoferritins/metabolism
Sex Factors

@article {pmid40246821,
year = {2025},
author = {Li, X and Chen, J and Yang, Y and Cai, H and Ao, Z and Xing, Y and Li, K and Yang, K and Guan, W and Friend, J and Lee, LP and Wang, N and Guo, F},
title = {Extracellular vesicle-based point-of-care testing for diagnosis and monitoring of Alzheimer's disease.},
journal = {Microsystems & nanoengineering},
volume = {11},
number = {1},
pages = {65},
pmid = {40246821},
issn = {2055-7434},
abstract = {Extracellular vesicles (EVs) show potential for early diagnosis of Alzheimer's disease (AD) and monitoring of its progression. However, EV-based AD diagnosis faces challenges due to the small size and low abundance of biomarkers. Here, we report a fully integrated organic electrochemical transistor (OECT) sensor for ultrafast, accurate, and convenient point-of-care testing (POCT) of serum EVs from AD patients. By utilizing acoustoelectric enrichment, the EVs can be quickly propelled, significantly enriched, and specifically bound to the OECT detection area, achieving a gain of over 280 times response in 30 s. The integrated POCT sensor can detect serum EVs from AD patients with a limit of detection as low as 500 EV particles/mL and a reduced detection time of just two minutes. Furthermore, the integrated POCT sensors were used to monitor AD progression in an AD mouse model by testing the mouse Aβ EVs at different time courses (up to 18 months) and compared with the Aβ accumulation using high-resolution magnetic resonance imaging (MRI). This innovative technology has the potential for accurate and rapid diagnosis of Alzheimer's and other neurodegenerative diseases, and monitoring of disease progression and treatment response.},
}

@article {pmid40246680,
year = {2025},
author = {Akter, S and Liu, Z and Simoes, EJ and Rao, P},
title = {Using machine learning and electronic health record (EHR) data for the early prediction of Alzheimer's Disease and Related Dementias.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100169},
doi = {10.1016/j.tjpad.2025.100169},
pmid = {40246680},
issn = {2426-0266},
abstract = {BACKGROUND: Over 6 million patients in the United States are affected by Alzheimer's Disease and Related Dementias (ADRD). Early detection of ADRD can significantly improve patient outcomes through timely treatment.

OBJECTIVE: To develop and validate machine learning (ML) models for early ADRD diagnosis and prediction using de-identified EHR data from the University of Missouri (MU) Healthcare.

DESIGN: Retrospective case-control study.

SETTING: The study used de-identified EHR data provided by the MU NextGen Biomedical Informatics, modeled with the PCORnet Common Data Model (CDM).

PARTICIPANTS: An initial cohort of 380,269 patients aged 40 or older with at least two healthcare encounters was narrowed to a final dataset of 4,012 ADRD cases and 119,723 controls.

METHODS: Six ML classifier models: Gradient-Boosted Trees (GBT), Light Gradient-Boosting Machine (LightGBM), Random Forest (RF), eXtreme Gradient-Boosting (XGBoost), Logistic Regression (LR), and Adaptive Boosting (AdaBoost) were evaluated using Area Under the Receiver Operating Characteristic Curve (AUC-ROC), accuracy, sensitivity, specificity, and F1 score. SHAP (SHapley Additive exPlanations) analysis was applied to interpret predictions.

RESULTS: The GBT model achieved the best AUC-ROC scores of 0.809-0.833 across 1- to 5-year prediction windows. SHAP analysis identified depressive disorder, age groups 80-90 yrs and 70-80 yrs, heart disease, anxiety, and the novel risk factors of sleep apnea, and headache.

CONCLUSION: This study underscores the potential of ML models for leveraging EHR data to enable early ADRD prediction, supporting timely interventions, and improving patient outcomes. By identifying both established and novel risk factors, these findings offer new opportunities for personalized screening and management strategies, advancing both clinical and informatics science.},
}

@article {pmid40248131,
year = {2023},
author = {Millar, CL and Iloputaife, I and Baldyga, K and Kuo, J and Tchkonia, T and Kirkland, JL and Travison, TG and Lipsitz, LA},
title = {Rationale and Design of STAMINA: Senolytics To Alleviate Mobility Issues and Neurological Impairments in Aging, A Geroscience Feasibility Study.},
journal = {Translational medicine of aging},
volume = {7},
number = {},
pages = {109-117},
pmid = {40248131},
issn = {2468-5011},
abstract = {The process of cellular senescence is hypothesized to play a critical role in the development of age-related mobility and cognitive impairments, both of which precede the development of Alzheimer's disease. Therefore, senolytic compounds that eliminate senescent cells represent an alternative strategy that may help improve mobility and cognition in older adults; however, clinical trials are lacking. The goal of this paper is to describe the rationale and study design of a 12-week single arm, open label, pre-post pilot study that administers intermittent doses of two senolytic compounds, Dasatinib and quercetin (DQ), in 12 older adults ≥ 65 years with slow gait speed (<1.0 m/sec) and mild cognitive impairment. Eligible participants are asked to take 1250 mg of and 100 mg of Dasatinib orally once a day for 2 days every 2 weeks, for 6 cycles over 12 consecutive weeks. Both physical and cognitive functional assessments are administered before treatment, as well as 6- and 12- weeks after treatment. Blood and urine samples are taken pre- and post-treatment to assess biomarkers of cellular senescence. The primary outcomes of this trial are feasibility and safety of the intervention, as well as preliminary efficacy on several clinical outcomes (e.g., cerebral blood flow velocity, gait speed, and biomarkers of cellular senescence). The study is approved by the Advarra IRB (#Pro00053594) and a Data Safety Monitoring Board. It is registered at Clinicaltrials.gov (Identifier:NCT05422885). The future results of this study may identify a novel approach for improving mobility and cognition in older adults, thereby preventing progression to Alzheimer's disease.},
}

@article {pmid40246050,
year = {2025},
author = {Neto, DCF and de Almeida, JSFD and Guimarães, SJA and Dos Santos, EM and Nascimento, MDDSB and de Azevedo-Santos, APS and França, TCC and LaPlante, SR and do Nascimento, CJ and Lima, JA},
title = {Guanylhydrazone and semicarbazone derivatives as potential prototypes for the design of cholinesterase inhibitors against Alzheimer's disease: biological evaluation and molecular modeling studies.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111515},
doi = {10.1016/j.cbi.2025.111515},
pmid = {40246050},
issn = {1872-7786},
abstract = {Despite being present in many drugs, guanylhydrazones and semicarbazones are two functional groups that have been little investigated as potential therapeutic strategies for the treatment of Alzheimer's disease (AD). For this reason, we initiated the synthesis and evaluation of these compounds as potential anticholinesterase agents, aiming to offer new alternatives for drug development against AD. In the severe phase of AD, butyrylcholinesterase (BChE) becomes the main enzyme responsible for the hydrolysis of acetylcholine (ACh). Therefore, in this project, we present the results of BChE inhibitory activity, enzyme kinetics, cytotoxicity, and molecular modeling studies for three guanylhydrazone and two semicarbazone derivatives that were previously synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Among the compounds tested, guanylhydrazones (1, 2, and 3) showed inhibitory activity against BChE, exhibiting a mixed non-competitive inhibition profile. Specifically, compound 2 (phenanthrenequinone) demonstrated superior inhibitory potency with an IC50 of 0.68 μM, compared to compound 1 (acridinone) with an IC50 of 3.87 μM, and compound 3 (benzodioxole) with an IC50 of 101.7 μM. In contrast, semicarbazones (4 and 5) showed no BChE inhibition up to the highest concentration tested (300 μM). Importantly, all five compounds were found to be non-cytotoxic. Our results suggest that these compounds have potential as drug prototypes targeting different phases of AD. Compounds 3, 4, and 5 may be more effective in the early phase, when AChE activity remains high; compound 1 could be useful in the intermediate phase; and compound 2 appears particularly promising for the severe phase, when BChE plays a more dominant role.},
}

@article {pmid40245823,
year = {2025},
author = {Zhao, Y and Wei, S and Liu, Y and He, X and Li, J and Gao, T and Wang, X and Li, Y and Nan, J and Wang, Y and Ma, Y},
title = {The prevalence and influencing factors of reversion from mild cognitive impairment to normal cognition: A systemic review and meta-analysis.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {63},
number = {},
pages = {379-387},
doi = {10.1016/j.gerinurse.2025.03.013},
pmid = {40245823},
issn = {1528-3984},
abstract = {OBJECTIVE: The aim was to investigate the pooled prevalence of reversion from mild cognitive impairment (MCI) to normal cognition people, and the influencing factors for reversion.

METHODS: PubMed, Embase, Web of Science, The Cochrane Library, Wanfang Database, China Knowledge Resource Integrated Database (CNKI), Weipu Database, SinoMed were systematically searched from the inception to June 1, 2023. Participants were diagnosis as MCI adults.

RESULTS: In total, 4075 studies were screened and data from 48 studies involving 31876 subjects were used in meta-analysis. The pooled prevalence of reversion from MCI to normal cognition was 31%. The following risk factors were associated with the reversion from MCI to normal cognition: education (low to high), age, Mini-Mental State Examination (MMSE), Functional Activities Questionnaire (FAQ), Auditory Verbal Learning Test (AVLT) delay recall test, Apolipoprotein E (APOE) positive, multiple domain impaired, live along, depression, doing house work daily/exercise once a week.

CONCLUSIONS: The study shows the pooled prevalence of reversion from MCI to normal cognition was high, and there are controllable factors. Understanding the controllable factors of reversion from MCI to normal cognition can provide the clinicians with the theoretical basis for the management and treatment of the patients.},
}

@article {pmid40245529,
year = {2025},
author = {Radin, DP and Cerne, R and Smith, JL and Witkin, JM and Lippa, A},
title = {Antipsychotic-like pharmacological profile of the low impact ampakine CX691 (farampator): Implications for the use of low impact ampakines in the treatment of schizophrenia.},
journal = {Journal of psychiatric research},
volume = {186},
number = {},
pages = {145-153},
doi = {10.1016/j.jpsychires.2025.04.019},
pmid = {40245529},
issn = {1879-1379},
abstract = {Ampakines, positive allosteric modulators of AMPA-glutamate receptors (AMPAR), have therapeutic implications in neuropsychiatric and neurological disorders in which AMPAR signaling is compromised such as Alzheimer's, ADHD, and schizophrenia. Low impact ampakines are a distinct subset of ampakines that only partially offset receptor desensitization and do not meaningfully alter binding affinity of AMPAR agonists, which may explain their lack of seizurogenic effects seen with other AMPAR positive modulators. Herein, we describe the preclinical pharmacology and antipsychotic activity of the low impact ampakine 1-(benzofurazan-5-ylcarbonyl)piperidine (CX691). CX691 moderately offsets desensitization in hippocampal patches, supporting its designation as a low impact ampakine and penetrates the blood-brain barrier. CX691 is more potent than well characterized high impact ampakines CX614 and CX546 and low impact ampakine CX516 in abrogating amphetamine-stimulated locomotor activity in Sprague Dawley rats. Low-dose CX691 synergistically reduces methamphetamine-induced locomotor activity when paired with approved antipsychotics clozapine and olanzapine. In rats treated chronically with amphetamine, CX691 retains antipsychotic activity whereas high doses of CX516 lack therapeutic effects. In contrast to haloperidol, CX691 is devoid of cataleptic activity at supratherapeutic doses in rats. CX691 enhances performance in the eight-arm radial maze, a spatial task that assesses hippocampal function, an activity of potential value for ameliorating cognitive deficits in schizophrenia. Taken together, these findings illustrate that low impact ampakines with improved potency might be useful therapeutic interventions in schizophrenic patients when given alone or as adjuncts to ongoing traditional antipsychotic drug therapies.},
}

@article {pmid40245392,
year = {2025},
author = {Ferré, F and Allassonnière, S and Chadebec, C and Minville, V},
title = {Generating Artificial Patients With Reliable Clinical Characteristics Using a Geometry-Based Variational Autoencoder: Proof-of-Concept Feasibility Study.},
journal = {Journal of medical Internet research},
volume = {27},
number = {},
pages = {e63130},
doi = {10.2196/63130},
pmid = {40245392},
issn = {1438-8871},
mesh = {Humans ; Feasibility Studies ; Proof of Concept Study ; *Deep Learning ; Autoencoder ; },
abstract = {BACKGROUND: Artificial patient technology could transform health care by accelerating diagnosis, treatment, and mapping clinical pathways. Deep learning methods for generating artificial data in health care include data augmentation by variational autoencoders (VAE) technology.

OBJECTIVE: We aimed to test the feasibility of generating artificial patients with reliable clinical characteristics by using a geometry-based VAE applied, for the first time, on high-dimension, low-sample-size tabular data.

METHODS: Clinical tabular data were extracted from 521 real patients of the "MAX" digital conversational agent (BOTdesign) created for preparing patients for anesthesia. A 3-stage methodological approach was implemented to generate up to 10,000 artificial patients: training the model and generating artificial data, assessing the consistency and confidentiality of artificial data, and validating the plausibility of the newly created artificial patients.

RESULTS: We demonstrated the feasibility of applying the VAE technique to tabular data to generate large artificial patient cohorts with high consistency (fidelity scores>94%). Moreover, artificial patients could not be matched with real patients (filter similarity scores>99%, κ coefficients of agreement<0.2), thus guaranteeing the essential ethical concern of confidentiality.

CONCLUSIONS: This proof-of-concept study has demonstrated our ability to augment real tabular data to generate artificial patients. These promising results make it possible to envisage in silico trials carried out on large cohorts of artificial patients, thereby overcoming the pitfalls usually encountered in in vivo trials. Further studies integrating longitudinal dynamics are needed to map patient trajectories.},
}

Humans
Feasibility Studies
Proof of Concept Study
*Deep Learning
Autoencoder

@article {pmid40245176,
year = {2025},
author = {Liu, Z and Zhang, J and Jiang, F and Liu, C and Shao, Y and Le, W},
title = {Biological Effects of Dietary Restriction on Alzheimer's Disease: Experimental and Clinical Investigations.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {4},
pages = {e70392},
doi = {10.1111/cns.70392},
pmid = {40245176},
issn = {1755-5949},
support = {YDZX20213100001002//Shanghai Municipal Central Government Funds for Guiding Local Scientific and Technological Development/ ; XLYC2403127//Young Top Talents in the Xingliao Talents Program of Liaoning Province/ ; 32220103006//National Natural Science Foundation of China/ ; 82271524//National Natural Science Foundation of China/ ; 2024RY003//Dalian Science and Technology Talent Innovation Support Program/ ; },
mesh = {*Alzheimer Disease/diet therapy/metabolism ; Humans ; Animals ; *Caloric Restriction/methods ; Brain/metabolism ; },
abstract = {BACKGROUNDS: Dementia can impose a heavy economic burden on both society and families. Alzheimer's disease (AD), the most prevalent form of dementia, is a complex neurodegenerative disease characterized by the abnormal deposition of extracellular amyloid β-protein (Aβ) and the aggregation of intracellular Tau protein to form neurofibrillary tangles (NFTs). Given the limited efficacy of pharmacological treatment, scientists have already paid more attention to non-pharmacological strategies, including dietary restriction (DR). DR refers to a nutritional paradigm aimed at promoting overall health by modifying the balance between energy consumption and expenditure. Studies have demonstrated that DR effectively extends the healthy lifespan, delays the aging process, and achieves promising results in the prevention and treatment of AD in preclinical studies.

METHODS: In this review we collected related studies and viewpoints by searching on PubMed database using the keywords. Most of the citations were published between 2015 and 2025. A few older literatures were also included due to their relevance and significance in this field.

RESULTS: We first provide a concise overview of the current therapeutic and preventive strategies for AD. Then, we introduce several specific DR protocols and their favorable effects on AD. Furthermore, the potential mechanisms underlying the benefits of DR on AD are discussed. Finally, we briefly highlight the role of DR in maintaining brain health.

CONCLUSION: This review may offer valuable insights into the development of innovative non-pharmacological strategies for AD treatment.},
}

*Alzheimer Disease/diet therapy/metabolism
Humans
Animals
*Caloric Restriction/methods
Brain/metabolism

@article {pmid40244500,
year = {2025},
author = {Lu, H and Xu, C and Liang, J},
title = {Evaluation of AccuBrain-based MRI quantitative analysis in diagnosing Alzheimer's disease and assessing behavioral and psychological symptoms of dementia.},
journal = {Aging clinical and experimental research},
volume = {37},
number = {1},
pages = {126},
pmid = {40244500},
issn = {1720-8319},
support = {2220001004730//the project of Foshan Science and Technology Bureau/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/psychology/diagnosis ; Male ; Female ; *Magnetic Resonance Imaging/methods ; Aged ; Retrospective Studies ; *Cognitive Dysfunction/diagnostic imaging/diagnosis ; Aged, 80 and over ; ROC Curve ; Atrophy ; Hippocampus/diagnostic imaging/pathology ; Neuropsychological Tests ; Biomarkers ; Middle Aged ; *Dementia/psychology/diagnostic imaging ; },
abstract = {AIM: Alzheimer's disease (AD) is a major cause of dementia, marked by cognitive decline and behavioral and psychological symptoms of dementia (BPSD). Early differentiation between AD, mild cognitive impairment (MCI), and healthy controls (HC) is essential for improving diagnostic accuracy and guiding effective treatment strategies.

METHODS: This retrospective study included 120 participants divided into AD (n = 40), MCI (n = 40), and HC (n = 40) groups. Brain MRI data were analyzed using the AccuBrain system to quantify AD Resemblance Atrophy Index (AD-RAI), Quantitative Medial Temporal Atrophy (QMTA), hippocampal volume, and white matter hyperintensities. Correlation analyses were conducted between imaging biomarkers and cognitive function scores (Mini-Mental State Examination, MMSE; Neuropsychiatric Inventory, NPI). Receiver operating characteristic (ROC) curve analysis was used to evaluated the diagnostic performance of the biomarkers.

RESULTS: AD patients had significantly higher AD-RAI (0.91 ± 0.25) and more pronounced hippocampal atrophy (0.36 ± 0.09) compared to MCI and HC (P < 0.001). Correlation analyses showed that AD-RAI and QMTA were negatively correlated with MMSE scores (r = -0.718, P < 0.001; r = -0.463, P < 0.001), while hippocampal volume was positively correlated with MMSE (r = 0.408, P < 0.001). ROC analysis revealed that AD-RAI had an AUC of 0.777 for distinguishing AD from MCI, while QMTA had an AUC of 0.938 for distinguishing AD from HC. BPSD patients exhibited higher AD-RAI (1.09 ± 0.18) and greater hippocampal atrophy, with ROC AUC > 0.9 for distinguishing BPSD from non-BPSD patients.

CONCLUSION: The AccuBrain MRI system demonstrated high sensitivity and diagnostic value in distinguishing AD from MCI and HC, as well as in identifying patients with BPSD. Correlation and ROC analyses support the use of these imaging biomarkers for early diagnosis and personalized treatment strategies in AD.},
}

Humans
*Alzheimer Disease/diagnostic imaging/psychology/diagnosis
Male
Female
*Magnetic Resonance Imaging/methods
Aged
Retrospective Studies
*Cognitive Dysfunction/diagnostic imaging/diagnosis
Aged, 80 and over
ROC Curve
Atrophy
Hippocampus/diagnostic imaging/pathology
Neuropsychological Tests
Biomarkers
Middle Aged
*Dementia/psychology/diagnostic imaging

@article {pmid40244482,
year = {2025},
author = {Das, A and Manna, R and Chowdhury, D and Sharma, D and Bodakhe, SH},
title = {Oxymatrine impedes Alzheimer's progression via the attenuation of hypercholesterolemia and fibrosis.},
journal = {Metabolic brain disease},
volume = {40},
number = {5},
pages = {187},
pmid = {40244482},
issn = {1573-7365},
mesh = {Animals ; *Alkaloids/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Quinolizines/pharmacology/therapeutic use ; Rats ; Male ; *Hypercholesterolemia/drug therapy/metabolism ; Disease Progression ; Fibrosis/drug therapy/metabolism ; Brain/drug effects/metabolism/pathology ; Maze Learning/drug effects ; Rats, Wistar ; Matrines ; },
abstract = {This study highlights the potential therapeutic benefits of oxymatrine (OMT), a quinolizidine alkaloid found in Sophora flavescens, for Alzheimer's disease (AD). This study connects the dots between metabolic and neuronal origins by exploring the effects of oxymatrine in slowing down hypercholesterolemic and fibrotic changes that contribute to cognitive deficits. In our study, laboratory rats were fed a high-cholesterol diet for eight weeks. Cognitive abilities were assessed weekly using Hebb's Williams Maze and Radial arm mazes. Additionally, intraperitoneal doses of OMT were administered (20 mg/kg, 40 mg/kg, and 80 mg/kg) for 21 days. Furthermore, using ELISA, plasma and brain oxysterols, transforming growth factor β, amyloid β, matrix metalloproteinase- 9, claudin- 5, and ATP Binding Cassette Transporter A1 levels were measured biweekly. High-density lipoprotein, low-density lipoprotein, aspartate aminotransferase, and alanine transaminase levels were estimated using diagnostic kits. The findings demonstrate that The administration of oxymatrine to experimental animals resulted in a dose-dependent synergistic decline in several biomarkers, including oxysterols, transforming growth factor β, amyloid β, matrix metalloproteinase- 9, low-density lipoprotein, aspartate aminotransferase, and alanine transaminase levels. At the same time, a concomitant increase in the levels of Claudin- 5, ATP Binding Cassette transporter A1, high-density lipoprotein, and antioxidants in the same animals was observed, especially at a dose of 80 mg/kg. This study aims to establish a link between metabolic and neural origins by investigating the effects of oxymatrine in reducing the progression of hypercholesterolemia and fibrosis, which contribute to cognitive impairment in AD. The research explores how oxymatrine regulates mediators involved in oxysterol production and fibrotic alterations in AD. Preliminary results suggest that oxymatrine has the potential to significantly delay the development and progression of AD, offering a promising treatment alternative for those affected by the disease. The findings of the present study strongly suggest that OMT effectively retards the progression of AD, which is commonly associated with the intake of high-cholesterol diets. Subsequent investigations ought to examine the molecular mechanisms behind oxymatrine's interaction with oxysterols and lipid metabolism, including sophisticated imaging methodologies and metabolomics. Longitudinal studies are essential to evaluate the long-term efficacy and safety of oxymatrine in both animal models and people. Exploring its possible synergistic effects with current medications may yield more effective therapeutic techniques. Identifying biomarkers for personalised medication may also be beneficial. Clinical trials and research on oxymatrine's potential as a prophylactic medication may yield significant insights.},
}

Animals
*Alkaloids/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology
*Quinolizines/pharmacology/therapeutic use
Rats
Male
*Hypercholesterolemia/drug therapy/metabolism
Disease Progression
Fibrosis/drug therapy/metabolism
Brain/drug effects/metabolism/pathology
Maze Learning/drug effects
Rats, Wistar
Matrines

@article {pmid40244274,
year = {2025},
author = {Ostergaard, JR},
title = {A New Perspective on Agitation in Alzheimer's Disease: A Potential Paradigm Shift.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
doi = {10.3390/ijms26073370},
pmid = {40244274},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/physiopathology/complications/therapy ; *Psychomotor Agitation/physiopathology/therapy/etiology ; Autonomic Nervous System/physiopathology ; Aged ; },
abstract = {Agitation is a common and difficult-to-manage neuropsychiatric syndrome in dementia. Recently, an association with the autonomous nervous system has been suggested. From the literature researched, however, only two studies investigating autonomic function concomitant to agitation situations appeared; one case series comprised two American veterans with vascular and Alzheimer's dementia, respectively, and in a case series of patients with CLN3 (juvenile neuronal ceroid lipofuscinosis), this was found to be the most common neurodegenerative disease leading to dementia in childhood. In both case series, the measurement of the autonomic system disclosed a parasympathetic withdrawal and sympathetic hyperactivity in the temporal context with agitated behavior. If the time-wise-related autonomic imbalance shown previously can be demonstrated in a larger cohort of patients with Alzheimer's disease, the use of transcutaneous vagal stimulation might be a potential paradigm shift in the treatment of agitation in Alzheimer's disease.},
}

Humans
*Alzheimer Disease/physiopathology/complications/therapy
*Psychomotor Agitation/physiopathology/therapy/etiology
Autonomic Nervous System/physiopathology
Aged

@article {pmid40244061,
year = {2025},
author = {Tseriotis, VS and Liampas, A and Lazaridou, IZ and Karachrysafi, S and Vavougios, GD and Hadjigeorgiou, GM and Papamitsou, T and Kouvelas, D and Arnaoutoglou, M and Pourzitaki, C and Mavridis, T},
title = {Repulsive Guidance Molecule-A as a Therapeutic Target Across Neurological Disorders: An Update.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
doi = {10.3390/ijms26073221},
pmid = {40244061},
issn = {1422-0067},
mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Nerve Tissue Proteins/metabolism/antagonists & inhibitors/genetics ; *GPI-Linked Proteins/metabolism/antagonists & inhibitors/genetics ; Molecular Targeted Therapy ; Neurodegenerative Diseases/metabolism/drug therapy ; },
abstract = {Repulsive guidance molecule-a (RGMa) has emerged as a significant therapeutic target in a variety of neurological disorders, including neurodegenerative diseases and acute conditions. This review comprehensively examines the multifaceted role of RGMa in central nervous system (CNS) pathologies such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuromyelitis optica spectrum disorder, spinal cord injury, stroke, vascular dementia, auditory neuropathy, and epilepsy. The mechanisms through which RGMa contributes to neuroinflammation, neuronal degeneration, and impaired axonal regeneration are herein discussed. Evidence from preclinical studies associate RGMa overexpression with negative outcomes, such as increased neuroinflammation and synaptic loss, while RGMa inhibition, particularly the use of agents like elezanumab, has shown promise in enhancing neuronal survival and functional recovery. RGMa's responses concerning immunomodulation and neurogenesis highlight its potential as a therapeutic avenue. We emphasize RGMa's critical role in CNS pathology and its potential to pave the way for innovative treatment strategies in neurological disorders. While preclinical findings are encouraging so far, further clinical trials are needed to validate the safety and efficacy of RGMa-targeted therapies.},
}

Humans
Animals
*Nervous System Diseases/metabolism/drug therapy
*Nerve Tissue Proteins/metabolism/antagonists & inhibitors/genetics
*GPI-Linked Proteins/metabolism/antagonists & inhibitors/genetics
Molecular Targeted Therapy
Neurodegenerative Diseases/metabolism/drug therapy

@article {pmid40243843,
year = {2025},
author = {Lui, M and Salamone, S and Pollastro, F and Mazzon, E and Artimagnella, O},
title = {Cannabinerol Restores mRNA Splicing Defects Induced by β-Amyloid in an In Vitro Model of Alzheimer's Disease: A Transcriptomic Study.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
doi = {10.3390/ijms26073113},
pmid = {40243843},
issn = {1422-0067},
support = {Current Research Funds 2024//Ministry of Health, Italy/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/drug therapy/pathology ; *Amyloid beta-Peptides/metabolism ; *Transcriptome/drug effects ; *RNA, Messenger/genetics ; *Alternative Splicing/drug effects ; *RNA Splicing/drug effects ; Cell Line, Tumor ; Gene Expression Profiling ; },
abstract = {Alzheimer's disease (AD) is the most common form of dementia, characterized by β-amyloid (Aβ) plaques and neurofibrillary tangles, leading to neuronal loss and cognitive impairments. Recent studies have reported the dysregulation of RNA splicing in AD pathogenesis. Our previous transcriptomic study demonstrated the neuroprotective effect of the phytocannabinoid cannabinerol (CBNR) against the cell viability loss induced by Aβ in differentiated SH-SY5Y cells. This study also highlighted the deregulation of genes involved in mRNA splicing after Aβ exposure or CBNR pre-treatment. Here, we investigated whether CBNR could restore the splicing defects induced by Aβ in an AD in vitro model. Using the rMATS computational tool for detecting differential alternative splicing events (DASEs) from RNA-Seq data, we obtained 96 DASEs regulated in both conditions and, remarkably, they were all restored by CBNR pre-treatment. The pathway analysis indicated an over-representation of the "Alzheimer's disease-amyloid secretase pathway". Additionally, we observed that Aβ exposure increased the frequency of retained introns (RIs) among the shared DASEs, and that this frequency returned to normality by CBNR pre-treatment. Interestingly, most of these RIs contain a premature in-frame stop codon within the RNA sequence. Finally, analyzing the DASE regions for miRNA hybridization, we found 33 potential DASE/miRNA interactions that were relevant in AD pathogenesis. These findings revealed a novel trans-gene regulation by CBNR, potentially explaining part of its neuroprotective role. This is the first study demonstrating the involvement of a cannabinoid in the regulation of mRNA splicing in an AD model.},
}

Humans
*Alzheimer Disease/genetics/metabolism/drug therapy/pathology
*Amyloid beta-Peptides/metabolism
*Transcriptome/drug effects
*RNA, Messenger/genetics
*Alternative Splicing/drug effects
*RNA Splicing/drug effects
Cell Line, Tumor
Gene Expression Profiling

@article {pmid40243772,
year = {2025},
author = {Mosalam, EM and Atya, SM and Mesbah, NM and Allam, S and Mehanna, ET},
title = {Neuroprotective Effects of Cilomilast and Chlorogenic Acid Against Scopolamine-Induced Memory Deficits via Modulation of the cAMP/PKA-CREB-BDNF Pathway.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
doi = {10.3390/ijms26073108},
pmid = {40243772},
issn = {1422-0067},
mesh = {Animals ; Brain-Derived Neurotrophic Factor/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Scopolamine/adverse effects ; Male ; Cyclic AMP/metabolism ; *Memory Disorders/drug therapy/chemically induced/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; *Chlorogenic Acid/pharmacology ; Cyclic AMP Response Element-Binding Protein/metabolism ; *Signal Transduction/drug effects ; Disease Models, Animal ; Phosphodiesterase 4 Inhibitors/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, neuroinflammation and neuronal damage. This study aimed to investigate the neuroprotective effects of cilomilast (CILO), a phosphodiesterase-4 (PDE4) inhibitor, alone and in combination with chlorogenic acid (CGA), a natural polyphenol, against scopolamine (SCOP)-induced cognitive impairment in mice. Forty male albino mice were divided into five groups: normal control, SCOP control, CGA + SCOP, CILO + SCOP and CILO + CGA + SCOP. Behavioral assessments, including the Y-maze and pole climbing tests, demonstrated that SCOP significantly impaired cognition, while treatment with CILO and CGA reversed these deficits, with the combination group showing the greatest improvement. Histopathological analyses revealed that CILO and CGA reduced neuronal damage and amyloid beta (Aβ) accumulation. Immunohistochemical and biochemical assessments confirmed a decrease in neuroinflammatory markers, including tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa B (NF-κB). Molecular analyses showed that CILO restored cyclic adenosine monophosphate (cAMP) levels, leading to activation of protein kinase A (PKA), cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), key regulators of neuronal plasticity and survival. CGA enhanced these effects by further inhibiting PDE4, amplifying the neuroprotective response. These findings suggest that PDE4 inhibitors, particularly in combination with CGA, may represent promising therapeutic strategies for AD-related cognitive impairment.},
}

Animals
Brain-Derived Neurotrophic Factor/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
Mice
Scopolamine/adverse effects
Male
Cyclic AMP/metabolism
*Memory Disorders/drug therapy/chemically induced/metabolism
Cyclic AMP-Dependent Protein Kinases/metabolism
*Chlorogenic Acid/pharmacology
Cyclic AMP Response Element-Binding Protein/metabolism
*Signal Transduction/drug effects
Disease Models, Animal
Phosphodiesterase 4 Inhibitors/pharmacology

@article {pmid40243521,
year = {2025},
author = {Palachai, N and Buranrat, B and Noisa, P and Mairuae, N},
title = {Oroxylum indicum (L.) Leaf Extract Attenuates β-Amyloid-Induced Neurotoxicity in SH-SY5Y Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
doi = {10.3390/ijms26072917},
pmid = {40243521},
issn = {1422-0067},
support = {//Thailand Science Research and Innovation/ ; },
mesh = {Humans ; *Plant Extracts/pharmacology/chemistry ; *Amyloid beta-Peptides/toxicity ; *Plant Leaves/chemistry ; *Neuroprotective Agents/pharmacology/chemistry ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Cell Survival/drug effects ; *Bignoniaceae/chemistry ; Caspase 3/metabolism ; Antioxidants/pharmacology ; *Peptide Fragments/toxicity ; Neurons/drug effects/metabolism ; Malondialdehyde/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by the presence of amyloid-beta (Aβ) plaques, which trigger oxidative stress and neuronal cell death. The present study investigated the neuroprotective effects of Oroxylum indicum (L.) leaf (OIL) extract against Aβ-induced oxidative stress and cellular damage in SH-SY5Y cells. The cells were treated with OIL extract with and without Aβ25-35, and their viability was investigated. Moreover, the mechanism of action of OIL was assessed by determining caspase-3 levels, reactive oxygen species (ROS) and malondialdehyde (MDA) levels, enzymatic activity of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), phosphorylation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and cAMP-responsive element-binding protein (CREB), and expression of B-cell lymphoma-2 (Bcl-2) proteins. The results indicated that OIL reduced Aβ-induced neurotoxicity in a concentration-dependent manner, improving cell viability, reducing ROS levels and MDA production, increasing antioxidant enzyme activity of CAT, SOD, and GSH-Px, and decreasing caspase-3 expression. In addition, OIL enhanced phosphorylation of Akt, ERK1/2, and CREB and upregulated Bcl-2 protein expression. High-performance liquid chromatography (HPLC) analysis identified oroxylin A, baicalein, and chrysin as the major phenolic constituents of the OIL extract. The findings suggest that the extract holds promise as a therapeutic intervention against Aβ-induced neurotoxicity, offering potential implications for the treatment of AD. Further studies are needed to investigate the activity of OIL in primary neurons or in vivo.},
}

Humans
*Plant Extracts/pharmacology/chemistry
*Amyloid beta-Peptides/toxicity
*Plant Leaves/chemistry
*Neuroprotective Agents/pharmacology/chemistry
Cell Line, Tumor
Reactive Oxygen Species/metabolism
Oxidative Stress/drug effects
Cell Survival/drug effects
*Bignoniaceae/chemistry
Caspase 3/metabolism
Antioxidants/pharmacology
*Peptide Fragments/toxicity
Neurons/drug effects/metabolism
Malondialdehyde/metabolism

@article {pmid40243451,
year = {2025},
author = {Arsić, B and Petrović, S and Ilić, BS and Vrecl, M and Trobec, T and Sepčić, K and Frangež, R and Glišić, SM and Milićević, JS},
title = {Inhibitory Potential of Boscalid and Abamectin Towards Acetylcholinesterase and Butyrylcholinesterase: Computational and In Vitro Studies.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
doi = {10.3390/ijms26072865},
pmid = {40243451},
issn = {1422-0067},
support = {337-00-21/2020-09/19//Ministry of Education, Science and Technological Development of the Republic of Serbia/ ; contract numbers 451-03-47/2023-01/200124 and 451-03-66/2024-03/200124 (B. Arsić, S. Petrović), and 451-03-47/2023-01/200017 and 451-03-66/2024-03/200017 (S. M. Glišić, J. S. Milićević)//Ministry of Science, Technological Development and Innovations of the Republic of Serbia/ ; research programs P4-0053 and P1-0207//Slovenian Research and innovation Agency/ ; },
mesh = {*Butyrylcholinesterase/chemistry/metabolism ; Humans ; *Ivermectin/analogs & derivatives/chemistry/pharmacology ; *Cholinesterase Inhibitors/pharmacology/chemistry ; *Acetylcholinesterase/chemistry/metabolism ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; *Niacinamide/analogs & derivatives/chemistry/pharmacology ; },
abstract = {The growing demand for agricultural products has led to the misuse of pesticides, resulting in the use of higher concentrations of these substances. This has led to an increase in toxicity imposed on other beneficial organisms and to the bioaccumulation of toxic pesticide concentrations in the bodies of both pests and non-target organisms, as well as in their end users, including humans. In this study, the neurotoxic potential of the commonly used pesticides abamectin (an insecticide) and boscalid (a fungicide) was evaluated. Both in vitro and in silico studies showed that human butyrylcholinesterase is not a target for abamectins B1A and B1B. Boscalid showed a modest Glide score (-28.8 kJ/mol) and a considerably higher IC50 (308.8 µM) against human butyrylcholinesterase than the approved inhibitor (2-((1-(benzenesulfonyl)-1H-indol-4-yl)oxy)ethyl)(benzyl)amine (IC50 = 0.473 µM). However, due to its non-mutagenicity and low toxicity, structural analogues of boscalid might be considered as candidates for the symptomatic treatment of Alzheimer's disease. Molecular dynamics simulations over 100 ns confirmed the stability of boscalid within the active site of butyrylcholinesterase, where it maintained key interactions with catalytic residues such as Trp82 and His438. These findings highlight its potential as a starting point for structure-based drug design strategies aimed at optimizing cholinesterase inhibitors with improved pharmacokinetic properties. According to absorption, distribution, metabolism, elimination, and toxicity studies, boscalid is orally active, which cannot be attributed to abamectins B1A and B1B.},
}

*Butyrylcholinesterase/chemistry/metabolism
Humans
*Ivermectin/analogs & derivatives/chemistry/pharmacology
*Cholinesterase Inhibitors/pharmacology/chemistry
*Acetylcholinesterase/chemistry/metabolism
Molecular Dynamics Simulation
Molecular Docking Simulation
*Niacinamide/analogs & derivatives/chemistry/pharmacology

@article {pmid40243219,
year = {2025},
author = {Xu, J and Liu, B and Shang, G and Feng, Z and Yang, H and Chen, Y and Yu, X and Mao, Z},
title = {Efficacy and Safety of Bilateral Deep Brain Stimulation (DBS) for Severe Alzheimer's Disease: A Comparative Analysis of Fornix Versus Basal Ganglia of Meynert.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {4},
pages = {e70285},
doi = {10.1111/cns.70285},
pmid = {40243219},
issn = {1755-5949},
support = {2021ZD0200407//STI 2030-Major Projects/ ; },
mesh = {Humans ; *Deep Brain Stimulation/methods/adverse effects ; Male ; Female ; *Alzheimer Disease/therapy/psychology ; *Fornix, Brain/physiology ; Aged ; Middle Aged ; Prospective Studies ; Treatment Outcome ; *Basal Nucleus of Meynert/physiology ; },
abstract = {BACKGROUND: Deep brain stimulation (DBS) is a novel therapy for severe Alzheimer's disease (AD). However, there is an ongoing debate regarding the optimal target for DBS, particularly the fornix and the basal ganglia of Meynert (NBM).

OBJECTIVE: This study aimed to investigate the safety and efficacy of DBS for severe AD and to compare the fornix and the NBM as potential targets.

METHODS: We conducted a prospective, nonrandomized clinical study involving 20 patients with severe AD (MMSE score 0 to 10, CDR level 3) from January 2015 to August 2022, comprising 12 males and eight females, with a mean age of 59.05 ± 6.45 years. All patients underwent DBS treatment, among which 14 received bilateral fornix implantation, while six received bilateral implantation in the NBM. Electrical stimulation commenced 1 month postoperatively. We assessed the patients before surgery, followed by evaluations at 1 month, 3 months, 6 months, and 12 months poststimulation. Primary outcome measures focused on changes in cognitive function, assessed using the MMSE, MoCA, ADAS-Cog, and CDR scales. Secondary measures encompassed quality of life, caregiver burden, neuropsychiatric symptoms, and sleep disturbances, evaluated through the BI, FAQ, FIM, ZBI, NPI, HAMA, HAMD, and PSQI scales.

RESULTS: All patients tolerated DBS well, with no serious adverse effects reported. Early on, DBS significantly improved cognitive function and quality of life. Long-term benefits include the improvement of neuropsychiatric symptoms and sleep disorders and the alleviation of caregiver burden. Comparison between DBS targeting the NBM and fornix revealed no significant differences in overall scale scores. However, upon deeper analysis, NBM-DBS exhibited a more pronounced improvement in neuropsychiatric symptoms, particularly in NPI scores.

CONCLUSION: DBS is a potential therapeutic approach for severe AD, capable of improving patients' cognitive function, quality of life, and neuropsychiatric symptoms. Notably, NBM-DBS showed distinct advantages in ameliorating neuropsychiatric symptoms, providing valuable insights for clinically selecting the optimal DBS target.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03115814.},
}

Humans
*Deep Brain Stimulation/methods/adverse effects
Male
Female
*Alzheimer Disease/therapy/psychology
*Fornix, Brain/physiology
Aged
Middle Aged
Prospective Studies
Treatment Outcome
*Basal Nucleus of Meynert/physiology

@article {pmid40242567,
year = {2025},
author = {Li, X and Singh, S and Rasouli, B and Lyons, J and Cocoros, NM and Platt, R and Abi-Elias, I and Gurwitz, JH},
title = {Generating real-world evidence in early Alzheimer's disease: Considerations for applying the target trial emulation framework to study the safety of anti-amyloid therapies.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70080},
pmid = {40242567},
issn = {2352-8737},
abstract = {UNLABELLED: Anti-amyloid beta monoclonal antibodies (anti-Aβ mAbs) have received approval from the US Food and Drug Administration for the treatment of patients with mild cognitive impairment or mild dementia due to Alzheimer's disease (collectively known as early AD) based on evidence from clinical trials. However, whether findings from these trials are generalizable to the real world is uncertain. We need reliable evidence on the real-world safety of these treatments to inform decision making for clinicians, patients, and caregivers. Using lecanemab as an exemplar, we outline the key considerations in designing and implementing an observational study on safety and utilization outcomes using established administrative healthcare claims data sources with the target trial emulation framework. The target trial emulation framework is a rigorous causal inference framework that minimizes common biases in observational studies. The approach proposed here can be applied to evaluation of additional mAbs as they become available.

HIGHLIGHTS: Little is known about real-world safety of anti-amyloid beta monoclonal antibodies for early Alzheimer's disease.Existing real-world data can support studies of their safety and utilization outcomes.Target trial emulation can guide the design of these studies while minimizing bias.We provide key design and analytical considerations for future studies.},
}

@article {pmid40242445,
year = {2025},
author = {Yan, L and Zhang, L and Xu, Z and Luo, Z},
title = {A real-world disproportionality analysis of FDA adverse event reporting system (FAERS) events for lecanemab.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1559447},
pmid = {40242445},
issn = {1663-9812},
abstract = {BACKGROUND: Lecanemab is a humanized murine IgG1 antibody. Recent Phase 3 clinical trials have demonstrated its ability to reduce brain amyloid-β (Aβ) load and slow cognitive decline in patients with early Alzheimer's disease (AD). However, since its approval, reports on adverse effects (AEs) associated with lecanemab have been limited. To better understand the AEs related to lecanemab and provide guidance for future clinical use, we analyzed lecanemab-associated AEs using data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).

METHODS: We extracted all AEs reports from the FAERS database for the period from the first quarter of 2023 to the third quarter of 2024. Using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) algorithms, we conducted a comprehensive analysis of lecanemab-related AEs, restricting the analysis to AEs with the role code of primary suspect (PS).

RESULTS: A total of 811 AEs reports related to lecanemab used in AD patients and 506 AEs in Non-AD patients were included. The preferred terms (PTs) identified as positive across all four algorithms included headache, Amyloid Related Imaging Abnormalities-oedema/effusion (ARIA-E), chills, Amyloid Related Imaging Abnormalities-haemosiderosis/microhaemorrhage (ARIA-H), fatigue, infusion-related reaction, nausea, pyrexia, pain, influenza like illness, and so on. Among these, ARIA-E, ARIA-H, brain oedema and status epilepticus were associated with Important Medical Events (IMEs) for AD patients, and brain oedema, cerebral haemorrhage, cerebral microhaemorrhage, subdural haematoma, ischaemic stroke, cerebral infarction were associated with IMEs for Non-AD patients. At the system organ class (SOC) level, the highest signal detection for lecanemab was observed in nervous system disorders among AD and Non-AD patients [ROR for AD: 2.42 (2.2-2.65); ROR for Non-AD: 6.97 (6.12-7.95)]. The median time to the occurrence of these AEs was 44 days after administration in AD patients and 30 days for Non-AD patients.

CONCLUSION: This study utilized the FAERS database to evaluate lecanemab-associated AEs in AD and non-AD patients, along with their temporal patterns post-marketing authorization, thereby establishing a foundation for subsequent clinical pharmacovigilance. A biweekly 10 mg/kg was identified as the optimal therapeutic dosage. ARIA emerged as frequent treatment-related AEs, with APOEɛ4 carriers demonstrating heightened susceptibility. This necessitates serial brain MRI surveillance for all patients during treatment, aimed not only at early ARIA detection but also vigilant monitoring of IMEs including cerebral haemorrhage, cerebral microhaemorrhages, subdural haematoma, cerebral edema, ischaemic stroke, and cerebral infarction. While AD patients predominantly exhibited non-specific clinical manifestations, non-AD cohorts showed elevated risks of stroke-related complications. Consequently, dynamic neurological deficit monitoring is indispensable for non-AD populations receiving lecanemab to mitigate adverse outcomes. Finally, comprehensive reassessment of anticoagulant or antiplatelet therapy indications is warranted in both AD and non-AD patients to reduce hemorrhagic risks.},
}

@article {pmid40242161,
year = {2025},
author = {Xie, W and Li, Y and Wang, X and Blokhina, E and Krupitsky, E and Vetrova, M and Hu, J and Yuan, TF and Chen, J and Wang, H and Chen, X},
title = {GABAB Receptor: Structure, Biological Functions, and Therapy for Diseases.},
journal = {MedComm},
volume = {6},
number = {5},
pages = {e70163},
pmid = {40242161},
issn = {2688-2663},
abstract = {Gamma-aminobutyric acid (GABA) B receptors (GABABRs) that acts slowly and maintains the inhibitory tone are versatile regulators in the complex nervous behaviors and their involvement in various neuropsychiatric disorders, such as anxiety, epilepsy, pain, drug addiction, and Alzheimer's disease. Additional study advances have implied the crucial roles of GABABRs in regulating feeding-related behaviors, yet their therapeutic potential in addressing the neuropsychiatric disorders, binge eating, and feeding-related disorders remains underutilized. This general review summarized the physiological structure and functions of GABABR, explored the regulation in various psychiatric disorders, feeding behaviors, binge eating, and metabolism disorders, and fully discussed the potential of targeting GABABRs and its regulator-binding sites for the treatment of different psychiatric disorders, binge eating and even obesity. While agonists that directly bind to GABABR1 have some negative side effects, positive allosteric modulators (PAMs) that bind to GABABR2 demonstrate excellent therapeutic efficacy and tolerability and have better safety and therapeutic indexes. Moreover, phosphorylation sites of downstream GABABRs regulators may be novel therapeutic targets for psychiatric disorders, binge eating, and obesity. Further studies, clinical trials in particular, will be essential for confirming the therapeutic value of PAMs and other agents targeting the GABABR pathways in a clinical setting.},
}

@article {pmid40241196,
year = {2025},
author = {Lim, J and Gu, H and Sang, H and Jeong, SJ and Kim, HI},
title = {Impact of nucleos(t)ide analogue therapy on the incidence of Alzheimer's disease in patients with chronic hepatitis B virus infection.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {84},
pmid = {40241196},
issn = {1758-9193},
support = {2023//The Korean Association for the Study of the Liver and The Korean Liver Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology/prevention & control ; Male ; Female ; *Hepatitis B, Chronic/drug therapy/epidemiology ; Retrospective Studies ; Incidence ; Middle Aged ; Aged ; *Antiviral Agents/therapeutic use ; Republic of Korea/epidemiology ; *Nucleosides/therapeutic use ; Adult ; Cohort Studies ; },
abstract = {BACKGROUND: Long-term therapy with nucleos(t)ide analogs (NUCs) is inevitable for chronic hepatitis B (CHB) patients. However, how NUC therapy on the developing Alzheimer's disease (AD) in these patients remains controversial.

METHODS: This retrospective cohort study used the Korean National Health Insurance Service claims database from January 1, 2013, to December 31, 2013, treatment naïve CHB patients and those without previously diagnosed with AD. Participants were followed from the index date until either the diagnosis of AD or the study's conclusion on December 31, 2021. The primary outcome was the incidence of AD, compared between the group with initiated NUC therapy (n = 18,365) at cohort entry and the group without NUC therapy (n = 212,820).

RESULTS: During the study, 416 patients were diagnosed with AD. After propensity-score matching (18,365 pairs), the 5- to 7-year follow-up showed a significantly lower hazard ratio (HR) in the NUC-treated group compared to the untreated group (HR 0.31-0.40), with HRs remaining constant over time. Subgroup analysis showed more pronounced benefits of NUC therapy in patients under 65 years (HRs: 0.22 vs. 1.23; P < 0.05) and those without dyslipidemia (HRs: 0.14 vs. 1.09; P < 0.05). Protective effects were also observed across subgroups with hypertension, chronic kidney disease, heart disease, and a history of brain trauma, consistent with AD risk factor trends.

CONCLUSIONS: Our study analyses suggest that NUC therapy appears to have a protective effect against the development of AD in patients with CHB.},
}

Humans
*Alzheimer Disease/epidemiology/prevention & control
Male
Female
*Hepatitis B, Chronic/drug therapy/epidemiology
Retrospective Studies
Incidence
Middle Aged
Aged
*Antiviral Agents/therapeutic use
Republic of Korea/epidemiology
*Nucleosides/therapeutic use
Adult
Cohort Studies

@article {pmid40240849,
year = {2025},
author = {Makin, S},
title = {The future of Alzheimer's treatment.},
journal = {Nature},
volume = {640},
number = {8059},
pages = {S4-S6},
pmid = {40240849},
issn = {1476-4687},
}

@article {pmid40240844,
year = {2025},
author = {Vargas-Parada, L},
title = {The unusual genetic inheritance that could change Alzheimer's treatment.},
journal = {Nature},
volume = {640},
number = {8059},
pages = {S7},
pmid = {40240844},
issn = {1476-4687},
}

@article {pmid40240764,
year = {2025},
author = {Kömür, M and Kıyan, HT and Öztürk, AA},
title = {Development of donepezil hydrochloride-loaded PLGA-based nanoparticles for Alzheimer's disease treatment.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {13184},
pmid = {40240764},
issn = {2045-2322},
support = {Project number: 2304S027, Project ID: 1956//Anadolu University Scientific Research Project Commission/ ; },
mesh = {*Donepezil/chemistry/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy ; *Nanoparticles/chemistry ; *Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Drug Liberation ; Particle Size ; Animals ; Drug Carriers/chemistry ; Humans ; Chick Embryo ; },
abstract = {In recent years, nanoparticle (NP) systems have demonstrated significant promise in pharmaceutical applications. This study focused on the development of donepezil hydrochloride-loaded PLGA-NPs, prepared using the 'Double Emulsion Solvent Evaporation' method. The impact of varying concentrations of polyvinyl alcohol-(PVA) in the aqueous phase and sonication time on NP characteristics was comprehensively examined. Results showed that increasing PVA concentration and sonication time resulted in a reduction in NP size, with an optimal formulation (I-DNP) achieving a particle size of 136.37 nm ± 0.93 and a PDI of 0.122 ± 0.011, indicating uniformity. The zeta potential was measured at - 24.17mV ± 1.21, confirming the electrostatic stability of the formulation, essential for long-term stability. Trehalose was incorporated to enhance stability, and gastrointestinal stability testing revealed that I-DNP degraded faster in acidic environments. The encapsulation efficiency reached 69.22 ± 4.84%, suggesting effective drug loading, and release studies exhibited a sustained release profile, with a Fickian and non-Fickian release mechanism. DSC, FT-IR, and [1]H-NMR analyses confirmed the encapsulation and structural integrity of the formulation. In biological activity studies, I-DNP exhibited potent anti-AChE and anti-BuChE activities, with Chorioallantoic Membrane (CAM) assays showing significant inhibition of angiogenesis. These findings highlight the potential of I-DNP as a promising therapeutic strategy for Alzheimer's disease, demonstrating its ability to enhance drug stability, controlled release, and potential blood-brain barrier (BBB) penetration. Future studies will focus on long-term stability testing and in vivo Alzheimer's models to further validate its clinical applicability. This research contributes to the advancement of nanoparticle-based drug delivery systems for neurodegenerative diseases, paving the way for innovative therapeutic approaches.},
}

*Donepezil/chemistry/pharmacology/administration & dosage
*Alzheimer Disease/drug therapy
*Nanoparticles/chemistry
*Polylactic Acid-Polyglycolic Acid Copolymer/chemistry
Drug Liberation
Particle Size
Animals
Drug Carriers/chemistry
Humans
Chick Embryo

@article {pmid40240583,
year = {2025},
author = {Sahoo, TA and Chand, J and Kandy, AT and Antony, S and Subramanian, G},
title = {Unravelling the Proteinopathic Engagement of α-Synuclein, Tau, and Amyloid Beta in Parkinson's Disease: Mitochondrial Collapse as a Pivotal Driver of Neurodegeneration.},
journal = {Neurochemical research},
volume = {50},
number = {3},
pages = {145},
pmid = {40240583},
issn = {1573-6903},
mesh = {*alpha-Synuclein/metabolism ; *tau Proteins/metabolism ; Humans ; *Parkinson Disease/metabolism/pathology ; *Mitochondria/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Animals ; *Nerve Degeneration/metabolism/pathology ; },
abstract = {Parkinson's disease is a complex neurological ailment manifested by dopaminergic neurodegeneration in the substantia nigra of the brain. This study investigates the molecular tripartite interaction between Lewy bodies, amyloid beta, and tau protein in the pathogenesis of Parkinson's disease. Lewy bodies which have been found as the important pathological hallmark in the degenerative neurons of Parkinson's patients, are mainly composed of α-synuclein. The accumulation of α-synuclein has been directly and indirectly linked to the severity and degree of progression of the disease. In addition, approximately 50% of Parkinson's disease cases are also described by hyperphosphorylation of tau protein indicating its significant involvement in the disease. The study further explains how α-synuclein, tau and amyloid beta can spread via cross-seeding mechanisms and accelerate each other's aggregation leading to neuronal death. Both GSK-3β and CDK5 are involved in phosphorylation which among other effects contributes to the misfolding of both α-synuclein and tau proteins that lead to neurodegeneration in Alzheimer's disease. Several mediators, that contribute to mitochondrial damage through elevated oxidative stress pathology are clearly described. Because of the increase in the incidence of Parkinson's disease, as predicted to be 17 million when the study was being conducted, studying these pathological mechanisms is very important in trying to establish treatments. This work contributes a path to finding a multi-target treatment regimen to alleviate the burden of this devastating disease.},
}

*alpha-Synuclein/metabolism
*tau Proteins/metabolism
Humans
*Parkinson Disease/metabolism/pathology
*Mitochondria/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Animals
*Nerve Degeneration/metabolism/pathology

@article {pmid40240578,
year = {2025},
author = {Du, K and Zuo, YL and Zhang, ZM and Li, A and Zuo, QH and Zhang, CY and Guo, R and Ping, C and Du, WS and Li, SM},
title = {The role of the hippocampus and SLC39A8 in chronic musculoskeletal pain-induced dementia: a Mendelian randomization study.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {13211},
pmid = {40240578},
issn = {2045-2322},
mesh = {Humans ; Mendelian Randomization Analysis ; *Dementia/etiology/genetics ; *Hippocampus/metabolism ; *Musculoskeletal Pain/complications/genetics ; *Chronic Pain/complications/genetics ; *Cation Transport Proteins/genetics/metabolism ; Polymorphism, Single Nucleotide ; },
abstract = {Despite observational studies suggesting a link between chronic musculoskeletal pain (CMP) and increased risk of cognitive decline and dementia, the causal nature of this relationship remains uncertain due to potential confounding factors and reverse causality. We employed two-sample Mendelian Randomization (TSMR), bidirectional MR, mediation MR, drug-target MR, and colocalization analysis, along with gene set enrichment and protein-protein interaction (PPI) analyses. TSMR assessed the causal associations between CMP and the risk of dementia and its subtypes, including Alzheimer's disease (AD), vascular dementia (VaD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and Parkinson's disease (PD). Bidirectional MR evaluated reverse causality, while mediation analyses identified potential mediators, focusing on neuroimaging and cognitive phenotypes. Drug-target MR investigated the role of the SLC39A8 gene, and colocalization analysis determined shared causal genetic variants. Gene set enrichment and PPI analyses elucidated the biological pathways implicated in the CMP-dementia relationship. Robust evidence established a causal relationship between chronic low back pain (LBP) and increased risk of PD, with knee osteoarthritis identified as a partial mediator, suggesting a pathway involving chronic inflammation. Bidirectional MR analysis revealed no evidence of reverse causality, further supporting the unidirectional causal link from LBP to PD. Colocalization analysis confirmed distinct genetic architectures for LBP and PD, while drug-target MR implicated the SLC39A8 gene as a potential mediator. Gene set enrichment and PPI analyses highlighted critical biological pathways, such as purine metabolism and glutamate receptor signaling. Suggestive evidence indicated potential causal links between limb pain and overall dementia, myalgia and VaD, as well as potential protective effects of Polymyalgia Rheumatica (PMR) against AD and rheumatism against PD. This study reveals a complex causal relationship between CMP and neurodegenerative diseases, particularly the robust link between LBP and PD. The findings underscore the need for further research to elucidate the underlying mechanisms and inform targeted prevention and treatment strategies.},
}

Humans
Mendelian Randomization Analysis
*Dementia/etiology/genetics
*Hippocampus/metabolism
*Musculoskeletal Pain/complications/genetics
*Chronic Pain/complications/genetics
*Cation Transport Proteins/genetics/metabolism
Polymorphism, Single Nucleotide

@article {pmid40239917,
year = {2025},
author = {Zhang, T and Zhang, Y and Chameau, P and Chen, T and Marmolejo-Garza, A and Douwenga, W and Dolga, AM and Kessels, HW and Schmidt, M and Eisel, ULM},
title = {Activation of Epac2 improves Aβ-induced impairment of memory retrieval in an acute model of Alzheimer's disease.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110468},
doi = {10.1016/j.neuropharm.2025.110468},
pmid = {40239917},
issn = {1873-7064},
abstract = {Impaired memory retrieval is one of the cognitive markers in the early stage of Alzheimer's Disease (AD). Previous studies report that exchange protein directly activated by cAMP 2 (Epac2) plays a specific and time-limited role in promoting memory retrieval. In this study, we investigated the effect of a novel Epac2 activator, S220, on neuronal and synaptic activities, and memory impairment in an acute AD mouse model. S220 treatment increased the firing rate of action potential and intracellular calcium in primary neurons. Moreover, S220 treatment increased synaptic currents in CA1 neurons. In the acute AD mouse model, intrahippocampal injection of amyloid-β (Aβ) oligomers impaired memory performance. Notably, administering S220 20 minutes before retention of contextual fear conditioning recovered the Aβ-induced memory impairment, suggesting an enhancing effect on memory retrieval. Collectively, our data demonstrate that the novel Epac2 activator S220 promotes synaptic communication and neuronal firing, and thereby improves Aβ-induced memory impairment via enhancing memory retrieval, indicating the role of Epac2 as a potential treatment target for AD.},
}

@article {pmid40237798,
year = {2025},
author = {Ahmed, HS},
title = {Neuropharmacological effects of calycosin: a translational review of molecular mechanisms and therapeutic applications.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {40237798},
issn = {1432-1912},
abstract = {Calycosin, a naturally occurring isoflavonoid found predominantly in Astragalus membranaceus, exhibits significant therapeutic potential in various neurological conditions. Its multifaceted bioactive properties-antioxidant, anti-inflammatory, and anti-apoptotic-position it as a promising candidate for neuroprotection and neuroregeneration. This review explores calycosin's mechanisms of action, including its modulation of key signaling pathways such as HMGB1/TLR4/NF-κB (high mobility group box 1/toll-like receptor 4/nuclear factor kappa B), phosphatidylinositol-3-kinase (PI3 K)/Akt, ERK1/2 (extracellular signal-regulated kinase 1/2), and Hsp90/Akt/p38. In cerebral ischemia/reperfusion injury, calycosin reduces oxidative stress markers like ROS (reactive oxygen species) and MDA (malondialdehyde), enhances antioxidant enzymes (SOD (superoxide dismutase) and GPX (glutathione peroxidase)), and downregulates pro-inflammatory cytokines (TNF-α, IL-1β) through the HMGB1/TLR4/NF-κB pathway. It also inhibits autophagy via the STAT3/FOXO3a pathway and apoptosis by modulating Bax and Bcl-2 expression. In neuro-oncology, calycosin inhibits glioblastoma cell migration and invasion by modulating the TGF-β-mediated mesenchymal properties and suppressing the c-Met and CXCL10 signaling pathways. Additionally, it enhances the efficacy of temozolomide in glioma treatment through apoptotic pathways involving caspase-3 and caspase-9. Calycosin shows promise in Alzheimer's disease by reducing β-amyloid production and tau hyperphosphorylation via the GSK-3β pathway and improving mitochondrial function through the peroxisome proliferator-activated receptor gamma coactivator 1-Alpha (PGC-1α)/mitochondrial transcription factor A (TFAM) signaling pathway. In Parkinson's disease, calycosin mitigates oxidative stress, prevents dopaminergic neuronal death, and reduces neuroinflammation by inhibiting the TLR/NF-κB and MAPK pathways. It has also shown therapeutic potential in meningitis and even neuroprotective effects against hyperbilirubinemia-induced nerve injury. Despite these promising findings, further research, including detailed mechanistic studies and clinical trials, is needed to fully understand calycosin's therapeutic mechanisms and validate its potential in human subjects. Developing advanced delivery systems and exploring synergistic therapeutic strategies could further enhance its clinical application and effectiveness.},
}

@article {pmid40237393,
year = {2025},
author = {Brendborg, N and Febbraio, MA},
title = {Intervention points for the role of physical activity in prevention and treatment of Alzheimer's disease.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP286747},
pmid = {40237393},
issn = {1469-7793},
support = {1194141//DHAC | National Health and Medical Research Council (NHMRC)/ ; },
abstract = {Alzheimer's disease (AD) is a growing global health challenge with limited pharmacological treatments. Epidemiological studies link regular physical activity with a lower risk of AD and cognitive decline in general, whereas randomized controlled trials show that aerobic exercise slows disease progression and improves cognitive function. However the underlying mechanisms remain incompletely understood. In this review we discuss five likely intervention points through which physical activity may influence AD progression and pathology: (1) reducing neuroinflammation and amyloid beta (Aβ) aggregation, (2) enhancing clearance of Aβ aggregates, (3) increasing neuronal resilience, (4) promoting hippocampal neurogenesis and (5) strengthening cognitive reserve. Understanding which of these mechanistic links are most likely to drive the AD-protective effects of exercise could help refine lifestyle-based interventions to complement pharmacological treatments and inform future prevention strategies.},
}

@article {pmid40237381,
year = {2025},
author = {Isik, M and Sari, HK and Caglayan, MG and Yilmaz, R and Derkus, B},
title = {Whispers in the Brain: Extracellular Vesicles in Neuropathology and the Diagnostic Alchemy of Neurological Diseases.},
journal = {The European journal of neuroscience},
volume = {61},
number = {8},
pages = {e70090},
doi = {10.1111/ejn.70090},
pmid = {40237381},
issn = {1460-9568},
support = {TSA-2023-2648//Ankara University Scientific Research Projects Coordination Unit/ ; TSA-2024-3217//Ankara University Scientific Research Projects Coordination Unit/ ; },
mesh = {Humans ; *Extracellular Vesicles/metabolism/pathology ; Animals ; *Nervous System Diseases/diagnosis/metabolism/pathology ; Biomarkers/metabolism ; *Brain/metabolism/pathology ; Neurodegenerative Diseases/diagnosis/metabolism ; },
abstract = {Extracellular vesicles (EVs) have emerged as pivotal mediators in neurological diseases, showcasing multifaceted potential roles ranging from pathogenesis to diagnosis. These nano-sized membranous structures, released by various cell types including neurons, astrocytes, and microglia, encapsulate a diverse cargo of proteins, lipids, RNA species, and even DNA fragments. In neuropathology, EVs contribute significantly to intercellular communication within the central nervous system (CNS), influencing physiological or pathological cascades. Through the transfer of bioactive molecules, EVs modulate neuroinflammation, neuronal survival, synaptic plasticity, and the propagation of protein aggregates characteristic of neurodegenerative disorders. Moreover, their presence in biofluids such as cerebrospinal fluid (CSF), blood, and urine reflects the pathophysiological state of the CNS, offering a window into the diagnosis, monitoring and treatment of neurological diseases. Recent advancements in EV isolation techniques, coupled with high-throughput omics technologies, have facilitated the profiling of EV cargo, enabling the identification of disease-specific biomarkers with high sensitivity and specificity. This review explores the intricate roles of EVs in neuropathology, highlighting their involvement in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and other neurological disorders. Furthermore, it delves into the diagnostic potential of EVs, discussing current challenges and prospects in harnessing EV-derived biomarkers for precision medicine in neurology. Ultimately, understanding the biology of EVs in neurological contexts promises transformative insights into disease mechanisms and therapeutic strategies, paving the way for innovative diagnostic tools and targeted interventions in clinical practice.},
}

Humans
*Extracellular Vesicles/metabolism/pathology
Animals
*Nervous System Diseases/diagnosis/metabolism/pathology
Biomarkers/metabolism
*Brain/metabolism/pathology
Neurodegenerative Diseases/diagnosis/metabolism

@article {pmid40237235,
year = {2025},
author = {Fertan, E and Lam, JYL and Albertini, G and Dewilde, M and Wu, Y and Akingbade, OES and Böken, D and English, EA and De Strooper, B and Klenerman, D},
title = {Lecanemab preferentially binds to smaller aggregates present at early Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {4},
pages = {e70086},
doi = {10.1002/alz.70086},
pmid = {40237235},
issn = {1552-5279},
support = {ERC-834682//European Union's Horizon 2020 Research and Innovation Program/ ; AARF-22-968623//Alzheimer's Association USA/ ; MR/Y014847/1//UK Medical Research Council/ ; //UK Dementia Research Institute/ ; //The Royal Society/ ; },
mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; Humans ; *Amyloid beta-Peptides/metabolism ; *Antibodies, Monoclonal, Humanized/metabolism/pharmacology ; *Brain/metabolism/pathology ; *Antibodies, Monoclonal/metabolism ; },
abstract = {INTRODUCTION: The monoclonal antibodies Aducanumab, Lecanemab, Gantenerumab, and Donanemab were developed for the treatment of Alzheimer's disease (AD).

METHODS: We used single-molecule detection and super-resolution imaging to characterize the binding of these antibodies to diffusible amyloid beta (Aβ) aggregates generated in-vitro and harvested from human brains.

RESULTS: Lecanemab showed the best performance in terms of binding to the small-diffusible Aβ aggregates, affinity, aggregate coating, and the ability to bind to post-translationally modified species, providing an explanation for its therapeutic success. We observed a Braak stage-dependent increase in small-diffusible aggregate quantity and size, which was detectable with Aducanumab and Gantenerumab, but not Lecanemab, showing that the diffusible Aβ aggregates change with disease progression and the smaller aggregates to which Lecanemab preferably binds exist at higher quantities during earlier stages.

DISCUSSION: These findings provide an explanation for the success of Lecanemab in clinical trials and suggests that Lecanemab will be more effective when used in early-stage AD.

HIGHLIGHTS: Anti amyloid beta therapeutics are compared by their diffusible aggregate binding characteristics. In-vitro and brain-derived aggregates are tested using single-molecule detection. Lecanemab shows therapeutic success by binding to aggregates formed in early disease. Lecanemab binds to these aggregates with high affinity and coats them better.},
}

*Alzheimer Disease/metabolism/drug therapy/pathology
Humans
*Amyloid beta-Peptides/metabolism
*Antibodies, Monoclonal, Humanized/metabolism/pharmacology
*Brain/metabolism/pathology
*Antibodies, Monoclonal/metabolism

@article {pmid40237061,
year = {2025},
author = {Öztürk, B and Demir, H and Günay, MS and Akdag, Y and Sahin, S and Gulsun, T},
title = {Photodynamic and Photothermal Therapies using Nanotechnology Approach in Alzheimer's Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X370790250317045223},
pmid = {40237061},
issn = {1875-6190},
abstract = {Alzheimer's disease is a neurodegenerative disease that impairs cognitive function. The incidence of Alzheimer's disease increases with the increase in the elderly population. Although the clear pathogenesis of Alzheimer's disease is not yet known, the formation of amyloid plaques and tau fibrils, diminished acetylcholine levels, and increased inflammation can be observed in patients. Alzheimer's disease, whose pathogenesis is not fully demonstrated, cannot be treated radically. Since it has been observed that only pharmacological treatment alone isn't sufficient, alternative approaches have become essential. Among these approaches, nanocarriers greatly facilitate the transport of drugs since the blood-brain barrier is an important obstacle to the penetration of drugs into the brain. Photosensitizers trigger activation after exposure to near-infrared radiation light of a suitable wavelength or laser light, resulting in the selective destruction of Aβ plaques. Photodynamic therapy and photothermal therapy have been investigated for their potential to inhibit Aβ plaques through photosensitizers. By encapsulating photosensitizers in nanocarriers, the limitations of photosensitizers can be overcome. By using these photosensitizers, near-infrared radiation fluorescence imaging can be used as a theranostic. In this review, potential treatment options for photodynamic therapy and photothermal therapy for Alzheimer's disease are summarised, and a simultaneous or combined approach is discussed, taking into account potential nanotheranostics.},
}