picture
RJR-logo

About | BLOGS | Portfolio | Misc | Recommended | What's New | What's Hot

About | BLOGS | Portfolio | Misc | Recommended | What's New | What's Hot

icon

Bibliography Options Menu

icon
QUERY RUN:
15 Jul 2025 at 01:36
HITS:
41432
PAGE OPTIONS:
Hide Abstracts   |   Hide Additional Links
NOTE:
Long bibliographies are displayed in blocks of 100 citations at a time. At the end of each block there is an option to load the next block.

Bibliography on: Alzheimer Disease — Current Literature

RJR-3x

Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 15 Jul 2025 at 01:36 Created: 

Alzheimer Disease — Current Literature

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. This bibliography runs a generic query on "Alzheimer" and then restricts the results to papers published in or after 2017.

Created with PubMed® Query: 2023:2025[dp] AND ( alzheimer*[TIAB] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

-->

RevDate: 2025-07-14

Yarbro JM, Shrestha HK, Wang Z, et al (2025)

Proteomic landscape of Alzheimer's disease: emerging technologies, advances and insights (2021 - 2025).

Molecular neurodegeneration, 20(1):83.

The advancements of proteomics technologies are shaping Alzheimer's disease (AD) research, revealing new molecular insights and improving biomarker discovery. Here, we summarize major AD proteomics studies since our 2021 review, focusing on disease mechanisms and biomarker identification. Enhanced sensitivity and throughput in proteome profiling have been driven by mass spectrometry (MS)-based approaches and affinity-based platforms (e.g., Olink and SomaScan). Emerging techniques, including single-cell, spatial, and single-molecule proteomics, provide unprecedented resolution in studying cellular heterogeneity and pathological microenvironments (e.g., amyloidome). Multi-cohort analyses of AD brain tissues have revealed consensus protein alterations (n = 866), identifying novel disease-associated proteins validated in functional studies (e.g., MDK/PTN, NTN1, SMOC1, GPNMB, NPTX2, NRN1, VGF, and U1 snRNP). Proteomic studies of AD biofluids have identified distinct disease subtypes, offering candidate proteins for early detection. Comparisons between human tissues and AD mouse models highlight shared pathways in amyloid pathology while underscoring limitations in recapitulating human disease. Combining proteomics with genomics enables protein quantitative trait locus (pQTL) analysis in AD, linking genetic risk factors to protein expression changes. Discrepancies between proteome and transcriptome suggest altered protein turnover in AD. Overall, AD proteomics continues to provide mechanistic insights into disease progression and potential biomarkers for precision medicine.

RevDate: 2025-07-14

Han ZZ, Kang SG, Gomez-Cardona E, et al (2025)

Expression of progerin enhances disease-related endpoints in a tau seeding reporter cell system.

GeroScience [Epub ahead of print].

Sporadic Alzheimer's disease and some forms of frontotemporal lobar degeneration (FTLD-tau) are neurological disorders of later life where cognitive deficits follow from the progressive accumulation of microtubule-associated tau protein. Disease-related tau accumulation is marked by altered subcellular distribution and rearrangement of this natively unstructured protein into alternative conformational forms, including highly organized fibrillar assemblies. With a partial analogy to effects seen in prion diseases, pathological tau conformers have a templating activity called seeding that may be measured in cellular and cell-free systems. Moreover, cellular systems and disease models can recapitulate "strain effects" wherein the same tau amino acid sequence can adopt markedly different conformations. Here we analyzed FTLD-tau conformers in cellular reporter systems expressing a pro-aging mutant form of the lamin A protein termed "progerin." Measured versus the baseline performance of a reporter system based on HEK293 cells, the addition of tau burden or progerin expression produced only mild changes in proteomic analyses or morphology, whereas application of both stressors produced a notable shift in ER stress and homeostasis, including increased levels of DNAJC10 and DNAJA2. The phenotypic effects scored here appear unrelated to the generation of new tau strains or to the type of strain input, insofar as progerin-expressing cells were more responsive to tau seeding by diverse brain samples containing different populations of tau conformers. Thus, premature aging and disease-associated tau conformers can exhibit an additive relationship in a model system.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Zolfaghari S, Joudaki A, Y Sarbaz (2025)

A hybrid learning approach for MRI-based detection of alzheimer's disease stages using dual CNNs and ensemble classifier.

Scientific reports, 15(1):25342.

Alzheimer's Disease (AD) and related dementias are significant global health issues characterized by progressive cognitive decline and memory loss. Computer-aided systems can help physicians in the early and accurate detection of AD, enabling timely intervention and effective management. This study presents a combination of two parallel Convolutional Neural Networks (CNNs) and an ensemble learning method for classifying AD stages using Magnetic Resonance Imaging (MRI) data. Initially, these images were resized and augmented before being input into Network 1 and Network 2, which have different structures and layers to extract important features. These features were then fused and fed into an ensemble learning classifier containing Support Vector Machine, Random Forest, and K-Nearest Neighbors, with hyperparameters optimized by the Grid Search Cross-Validation technique. Considering distinct Network 1 and Network 2 along with ensemble learning, four classes were identified with accuracies of 95.16% and 97.97%, respectively. However, using the derived features from both networks resulted in an acceptable classification accuracy of 99.06%. These findings imply the potential of the proposed hybrid approach in the classification of AD stages. As the evaluation was conducted at the slice-level using a Kaggle dataset, additional subject-level validation and clinical testing are required to determine its real-world applicability.

RevDate: 2025-07-14

Ardura-Fabregat A, Bosch LFP, Wogram E, et al (2025)

Response of spatially defined microglia states with distinct chromatin accessibility in a mouse model of Alzheimer's disease.

Nature neuroscience [Epub ahead of print].

Microglial spatial heterogeneity remains a crucial yet not fully answered question in the context of potential cell-directed therapies for Alzheimer's disease (AD). There is an unclear understanding of the dynamics of distinct microglia states adjacent to or far from amyloid-beta (Aβ) plaques and their contributions to neurodegenerative diseases. Here we combine multicolor fluorescence cell fate mapping, single-cell transcriptional analysis, epigenetic profiling, immunohistochemistry and computational modeling to comprehensively characterize the relation of plaque-associated microglia (PAM) and non-plaque-associated microglia (non-PAM) in a mouse model of AD. We show that non-PAM are a distinct and highly dynamic microglial state, transitioning to PAM after Aβ plaque deposition in female mice. Non-PAM modulate the cell population expansion in response to amyloid deposition and rapidly respond to environmental cues. Indeed, Csf1 signaling modulates non-PAM-to-PAM transition during disease progression. Our data suggest that microglia states and their dynamics between each other can have distinct contributions to disease, and they may be targeted for the treatment of AD.

RevDate: 2025-07-14

Freudenberg-Hua Y, Giliberto L, d'Abramo C, et al (2025)

Differential associations of APOE and TREM2 variants with glial fibrillary acidic protein and neurofilament light in plasma of UK Biobank participants support distinct disease mechanisms.

Molecular psychiatry [Epub ahead of print].

Plasma levels of glial fibrillary acidic protein (GFAP) and neurofilament light (NEFL) are key dementia biomarkers. GFAP and NEFL represent different underlying disease processes, i.e. astrocytic activation vs. neuronal damage. The associations of established genetic risk variants with these biomarkers may reflect time course and mechanisms by which the respective genes influence disease risk. Therefore, we investigated the association of the established high-effect dementia variants in APOE and TREM2 with these biomarkers, in a large population cohort of over 50,000 participants from the UK Biobank (UKB). The results show that APOE4 is associated with elevated levels of plasma GFAP, and to a lesser extent, NEFL. The APOE4 effect on GFAP increases with age and the number of APOE4 alleles. The risk variants R47H and R62H in TREM2 are associated with higher NEFL levels, but not with GFAP, and the effect sizes do not increase with age. In contrast, the protective APOE2 allele showed no effect on GFAP or NEFL. In conclusion, we find that major genetic risk factors for Alzheimer's disease exhibit distinct patterns of effect on these biomarkers, with APOE4 primarily affecting astrocyte activation starting in midlife, while TREM2 variants affect NEFL but not GFAP, and the protective effects of APOE2 are not captured by either of these biomarkers.

RevDate: 2025-07-14

He H, Ai R, Fang EF, et al (2025)

The Rab3 family proteins in age-related neurodegeneration: unraveling molecular pathways and potential therapeutic targets.

npj aging, 11(1):64.

The Rab3 protein family is composed of a series of small GTP-binding proteins, including Rab3a, Rab3b, Rab3c, and Rab3d, termed Rab3s. They play crucial roles in health, including in brain function, such as through the regulation of synaptic transmission and neuronal activities. In the high-energy-demanding and high-traffic neurons, the Rab3s regulate essential cellular processes, including trafficking of synaptic vesicles and lysosomal positioning, which are pivotal for the maintenance of synaptic integrity and neuronal physiology. Emerging findings suggest that alterations in Rab3s expression are associated with age-related neurodegenerative pathologies, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, among others. Here, we provide an overview of how Rab3s dysregulation disrupts neuronal homeostasis, contributing to impaired autophagy, synaptic dysfunction, and eventually leading to neuronal death. We highlight emerging questions on how Rab3s safeguards the brain and how their dysfunction contributes to the different neurodegenerative diseases. We propose fine-tuning the Rab3s signaling directly or indirectly, such as via targeting their upstream protein AMPK, holding therapeutic potential.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Raggi A, R Ferri (2025)

The Role of Vitamins in Neurodegeneration: A Brief Review of Mechanisms, Clinical Evidence, and Therapeutic Perspectives.

Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society, 25(4):e70071.

This review evaluates the role of vitamins in neurodegeneration. Low levels of B vitamins have been associated with cognitive decline. B vitamins may help inhibit amyloid plaque aggregation. Vitamin D deficiency has been linked to an increased risk of cognitive impairment, correlating with Alzheimer's pathology. Vitamin E may help delay Alzheimer's disease progression and support functional abilities. In Parkinson's disease, vitamin D shows promise in reducing dopaminergic neuron loss and improving motor and cognitive outcomes. Vitamin C reduces oxidative stress and preserves neuronal integrity. Vitamin K has gained attention for its role in cognitive health, with studies suggesting that higher levels may be linked to improved cognitive performance. In conclusion, a better understanding of the translational potential of these vitamins may inform preventive and therapeutic strategies for neurodegenerative diseases. Clinicians should consider vitamin supplementation for aging-related conditions. Further studies are needed to confirm its therapeutic potential and clarify underlying mechanisms in neurodegeneration.

RevDate: 2025-07-14

Chen M, Xue R, Zhang M, et al (2025)

Magnesium Depletion Score as a Novel Predictor of Cognitive Impairment: A Population-Based Cross-Sectional Study From NHANES.

Journal of the American Medical Directors Association pii:S1525-8610(25)00293-2 [Epub ahead of print].

OBJECTIVE: Magnesium (Mg) deficiency may accelerate neurodegenerative disease progression, but current cognitive impairment biomarkers have significant limitations. This study aimed to investigate the association between Mg depletion score (MDS) and cognitive impairment.

DESIGN: This study is a cross-sectional analysis using data from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) to examine the relationship between MDS and cognitive performance.

SETTING AND PARTICIPANTS: The study included 2768 participants aged 60 years and older from the NHANES dataset. Among them, 650 participants (23.48%) showed cognitive impairment on the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test, 700 (25.29%) on the Animal Fluency Test, and 676 (24.42%) on the Digit Symbol Substitution Test (DSST).

METHODS: Univariate and multivariate logistic regression models, multivariable linear regression models, and subgroup analyses were conducted to assess the association between MDS and cognitive performance.

RESULTS: Higher MDS scores were significantly associated with increased odds of cognitive impairment across all tests. Multivariable linear regression analysis revealed that MDS was significantly associated with cognitive impairment, particularly on the CREAD test (β, -0.71; 95% CI, 1.42-0.00) and the DSST (β, -2.78; 95% CI, 4.41 to -1.15). In contrast, the Animal Fluency Test demonstrated a weaker and less consistent association (β, -0.71; 95% CI, 1.48-0.06). Subgroup analyses showed that the association between MDS and cognitive impairment was particularly pronounced in individuals who were sedentary or had a dietary Mg intake ≤420 mg/d.

CONCLUSIONS AND IMPLICATIONS: MDS may serve as a predictor of cognitive impairment, with sedentary lifestyle and low dietary Mg intake strengthening this association. Further prospective studies are required to validate these findings. The study suggests that MDS could be an early marker for cognitive decline, with implications for early intervention in individuals with low Mg intake or sedentary behavior.

RevDate: 2025-07-14

Solorzano CS, Orini S, Festari C, et al (2025)

Clinical Pathways for Diagnosing Neurocognitive Disorders: Insights From Process Mining a Memory Clinic Cohort.

Journal of the American Medical Directors Association pii:S1525-8610(25)00291-9 [Epub ahead of print].

OBJECTIVES: Process mining (PM) has only recently been used in medicine. Its implementation in the dementia field could be valuable, considering the epidemiologic breadth of the condition and its economic implications. This proof-of-concept study aims to apply PM in the context of dementia to provide a realistic picture of patients' diagnostic pathways in a memory clinic.

DESIGN: Retrospective observational study.

SETTING AND PARTICIPANTS: A total of 539 medical charts were reviewed to obtain sociodemographic data and type and timing of diagnostic evaluations (eg, clinical or neuropsychological visits, imaging scans, and fluid biomarker analyses).

METHODS: We used a PM approach to create a process map from the clinical events and visualize the most common diagnostic pathways in the total cohort and subcohort of patients. PM techniques represent the temporal and dynamic sequence of clinical events in the patients' journeys, overcoming the traditional frequency analyses focused only on aggregate statistics and event distributions.

RESULTS: The results showed that the diagnosis was typically reached during the third clinical visit, following the results of instrumental examinations (ie, morphologic imaging, routine blood and neuropsychological examinations) and a first-line diagnostic biomarker. In mild cognitive impairment (MCI) and mild dementia (DEM) subcohorts, cerebrospinal fluid analyses are the most frequently used first-line biomarkers to ascertain a suspicion of Alzheimer disease (23%). Differential PM analyses revealed that the DEM subcohort underwent morphologic imaging before accessing the memory clinic more often than the MCI subcohort (P < .05).

CONCLUSIONS AND IMPLICATIONS: This preliminary use of PM algorithms in memory clinics shows promising results in visualizing and measuring real-world diagnostic pathways.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Röntgen A, Toprakcioglu Z, Morris OM, et al (2025)

Amyloid-β modulates the phase separation and aggregation of α-synuclein.

Proceedings of the National Academy of Sciences of the United States of America, 122(29):e2501987122.

The aggregation of amyloid-β (Aβ) and α-synuclein (αSyn) into insoluble proteinaceous deposits is a hallmark of Alzheimer's and Parkinson's diseases. Recent evidence suggests that these amyloidogenic proteins act in synergy, with their coaggregation frequently observed in these disorders. In this study, we investigate the interaction of Aβ and αSyn using various biophysical tools. In particular, we explore the cocondensation of Aβ with αSyn, elucidating the pathways through which Aβ modulates αSyn phase separation. We studied different variants of Aβ, focusing on the most prominent species, namely Aβ42 and Aβ40. We found that Aβ42 and Aβ40 have fundamentally different mechanistic effects on the kinetics of αSyn condensation. Aβ42 initially forms large aggregates that act as heterogeneous nucleation sites which initiate the phase separation of αSyn. In contrast, Aβ40 is sequestered into αSyn condensates where it accelerates the liquid-to-solid transition of αSyn into amyloid aggregates. All other Aβ variants we probed fell into one of these two mechanistic pathways, with Aβ37, Aβ39, and Aβ35-25 exhibiting similar behavior to Aβ40, whereas Aβ43 triggered nucleation processes similar to Aβ42. Given the complexity behind amyloid formation, it is key to understand how molecular partners can interact with one another. Our results thus illustrate the extreme sensitivity of protein mixtures and shed light on some of the mechanisms involved in the cocondensation and aggregation of Aβ with αSyn.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Zhang J, Zhang HL, Xu XR, et al (2025)

Targeting PBK with small-molecule 1-O-acetyl-4R,6S-britannilactone for the treatment of neuroinflammation.

Proceedings of the National Academy of Sciences of the United States of America, 122(29):e2502593122.

Neuroinflammation is a complex immunological phenomenon characterized by a dysregulated inflammatory response in the central nervous system (CNS) that can be triggered by various pathological injuries, such as toxins, which are involved in Parkinson's and Alzheimer's diseases (PD and AD), therefore, suppressing neuroinflammation serves as an effective treatment for CNS diseases. Herein, we found that natural soluble epoxide hydrolase (sEH) inhibitor 1-O-acetyl-4R,6S-britannilactone (AB) regulated mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways to suppress the microglial activation by regulating inflammation and autophagy in vitro and in vivo, contributing to the improvement of lipopolysaccharide (LPS)-mediated neuroinflammation. Protein microarray analysis indicated that AB could selectively target PDZ binding kinase (PBK) through covalently binding to C70, exhibiting a dissociation constant (Kd) of 0.62 μM, which was corroborated by subsequent chemical biology experiments. We gained a deeper understanding of the mechanistic by which AB interfered PBK function, specifically by disrupting its interaction with tumor necrosis factor alpha-induced protein-8 like-2 (TIPE2), blocking the serine 3 (S3) phosphorylation-mediated ubiquitylation and degradation of TIPE2. Additionally, our study revealed that PBK genetic deletion alleviated the course of LPS-mediated neuroinflammation in vitro and in vivo, and AB did not exhibit any extra effects in LPS-mediated PBK[-/-] mice. These findings first offered broader prospects for treating neuroinflammation by targeting PBK to repress inflammation and activate autophagy, suggesting that AB had the potential to serve as a direct inhibitor in the PBK-TIPE2 interaction.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Futai E, Shiina M, Dai Y, et al (2025)

Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by γ-Secretase.

Journal of visualized experiments : JoVE.

γ-Secretase is a protease complex embedded in the cell membrane, consisting of the catalytic presenilin subunits (PS1 or PS2) and three additional co-factors: nicastrin, Aph-1, and Pen2. It cleaves the transmembrane domains of type-I transmembrane proteins, such as the amyloid precursor protein (APP) and Notch. The cleavage of APP generates the amyloid β peptides (Aβ), which accumulate in patients with Alzheimer's disease. Despite significant research, the exact mechanism of this unique proteolysis, which occurs within the lipid bilayers, is still not fully understood. To study the enzymatic properties of γ-secretase, we have established a yeast reporter system using artificial γ-secretase substrates containing APP or Notch fragments fused to the transcriptional activator Gal4. The γ-secretase activity was evaluated by transcriptional activation of reporter genes upon Gal4 release from the membrane-bound substrates, as assessed by the growth of yeast or β-galactosidase activity. Furthermore, we have developed an in vitro assay to identify the different forms of Aβ produced from yeast microsomes. These yeast models provide a platform to screen mutations, genes, and compounds that affect γ-secretase function. By studying the loss of function properties of PS1 familial Alzheimer's disease (FAD) mutants, it is possible to screen for FAD suppressor mutations and γ-secretase modulators (GSMs), in addition to γ-secretase inhibitors (GSIs). In this report, we describe the genetic and biochemical methods used to study γ-secretase activity in the yeast system with the essential steps of the protocol for the video.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Ji H, Zhao Z, C Zhao (2025)

Unveiling Aducanumab's safety profile: A comprehensive pharmacovigilance analysis.

PloS one, 20(7):e0328076 pii:PONE-D-25-18621.

BACKGROUND: Aducanumab, a monoclonal antibody targeting amyloid-beta plaques, has been introduced as a pivotal therapeutic agent for Alzheimer's disease (AD). Although it offers promising benefits in the treatment of early-stage Alzheimer's disease, a thorough evaluation of its safety profile and potential adverse events (AEs) is essential to ensure patient safety.

METHODS: This retrospective pharmacovigilance study analyzed data from the FDA Adverse Event Reporting System (FAERS) database to evaluate AEs associated with Aducanumab. Employing a case/non-case methodology, the study utilized signal detection algorithms, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS), to identify AEs signals related to Aducanumab use.

RESULTS: The study encompassed a total of 11517459 reports, with 431 specifically citing Aducanumab. A substantial number of AEs were identified, particularly among the elderly population and those with pre-existing neurological conditions. The most frequently reported AEs were related to the nervous system, including "amyloid-related imaging abnormalities" such as edema/effusion and microhemorrhages. Other affected system organ classes (SOCs) included psychiatric disorders and general disorders and administration site conditions. Specific preferred terms (PTs) linked with Aducanumab included "confusional state," "disorientation," and "cerebral microhemorrhage." Unexpected AEs such as "subdural hematoma" and "head injury" were also noted, indicating a broader safety profile that requires further investigation.

CONCLUSIONS: The study's findings underscore the necessity for close monitoring of Aducanumab use, especially in elderly patients with AD. The identification of both expected and unexpected AEs emphasizes the need for ongoing pharmacovigilance and additional research to fully understand the safety profile of Aducanumab in clinical practice.

Strength: Utilized multiple signal detection algorithms (ROR, PRR, BCPNN, MGPS) to enhance robustness of pharmacovigilance findings. Limitation: Reliance on spontaneous FAERS reports, which are prone to underreporting, overreporting, and reporting bias.

RevDate: 2025-07-14

Li Z, Liu Y, Wei K, et al (2025)

Deconfounded and debiased estimation for high-dimensional linear regression under hidden confounding with application to omics data.

Bioinformatics (Oxford, England) pii:8200823 [Epub ahead of print].

MOTIVATION: A critical challenge in observational studies arises from the presence of hidden confounders in high-dimensional data. This leads to biases in causal effect estimation due to both hidden confounding and high-dimensional estimation. Some classical deconfounding methods are inadequate for high-dimensional scenarios and typically require prior information on hidden confounders. We propose a two-step deconfounded and debiased estimation for high-dimensional linear regression with hidden confounding.

RESULTS: First, we reduce hidden confounding via spectral transformation. Second, we correct bias from the weighted ℓ1 penalty, commonly used in high-dimensional estimation, by inverting the Karush-Kuhn-Tucker conditions and solving convex optimization programs. This deconfounding technique by spectral transformation requires no prior knowledge of hidden confounders. This novel debiasing approach improves over recent work by not assuming a sparse precision matrix, making it more suitable for cases with intrinsic covariate correlations. Simulations show that the proposed method corrects both biases and provides more precise coefficient estimates than existing approaches. We also apply the proposed method to a deoxyribonucleic acid methylation dataset from the Alzheimer's disease (AD) neuroimaging initiative database to investigate the association between cerebrospinal fluid tau protein levels and AD severity.

AVAILABILITY: The code for the proposed method is available on GitHub (https://github.com/Li-Zhaoy/Dec-Deb.git) and archived on Zenodo (DOI: 10.5281/zenodo.15478745).

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

RevDate: 2025-07-14

Luo J, Shang P, Tan Z, et al (2025)

Effects of accelerated intermittent theta-burst stimulation combined with cognitive training on brain function in amnestic mild cognitive impairment patients.

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology [Epub ahead of print].

OBJECTIVE: This double-blinded randomized trial investigated the effects of accelerated intermittent theta-burst stimulation (iTBS) and adaptive cognitive training on brain function in 24 patients with amnestic mild cognitive impairment (aMCI).

METHODS: Participants received real (n=12) or sham (n=12) iTBS targeting the left dorsolateral prefrontal cortex (DLPFC) thrice daily alongside cognitive training for 14 days. The Montreal Cognitive Assessment (MoCA), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and functional near-infrared spectroscopy (fNIRS) during rest and N-back tasks, which measure cognitive function and brain activity respectively, were administered pre-and post-intervention.

RESULTS: The active group demonstrated significant cognitive improvement. Compared to sham controls, postintervention fNIRS results revealed reduced global brain activation during the 1-back task in the active group, particularly in the left prefrontal cortex, and the brain activation correlated with reaction time. In the 2-back task after treatment, the active group exhibited decreased activation in the right motor cortex, while the sham group showed increased activation in the left motor cortex. The overall brain connectivity in the sham group enhanced following the intervention, with significant differences in the correlations between the left prefrontal cortex and left motor cortex between groups.

CONCLUSION: These findings suggest that the combined intervention can effectively promote cognitive performance and brain function in aMCI patients. iTBS causes enhanced functional engagement of the left DLPFC, which further facilitates neural efficiency and restores the capacity to modulate the allocation of neural resources rather than relying on global compensatory hyperactivation. These may be the underlying neural mechanisms for memory improvement in aMCI patients (Chinese Clinical Trial Registry: ChiCTR2400087943).

RevDate: 2025-07-14

Partoazar A, Goudarzi R, AR Dehpour (2025)

Therapeutic liposomes synergize with active molecules to enhance targeted therapy.

Journal of drug targeting [Epub ahead of print].

Liposomes composed of phospholipids (PLs) either alone or with an active molecule, can reveal a significant potential in the improvement of severe disorders such as Alzheimer's disease, osteoporosis, and inflammatory conditions. For instance, PLs exhibit anti-inflammatory, antioxidant, neuroprotective, and osteogenic properties in pathological conditions which accelerate the therapeutic effect of the drugs. These pharmacological properties can be modulated by the type and dose of PLs or liposome administration. They affect disorders through the signaling pathways, down or upregulation of gene expression, the balance of oxidative stress, and other biological mechanisms. Interestingly, liposomes containing essential PLs like phosphatidylserine with active molecules such as curcumin or alendronate could synergistically improve certain diseases like osteoporosis in experimental models. Accordingly, we aimed to highlight the unique advantages of various PLs or liposomes with an emphasis on their diverse therapeutic modalities and potentiation of liposomes in synergy with the cargos in experimental studies. These properties suggest a promising approach to enhance drug efficacy and mitigate the side effects through reduced drug usage in chronic diseases, however, their clinical translation requires further validation of safety and efficacy.

RevDate: 2025-07-14

Hamid M, Detroja TS, Tripathy SJ, et al (2025)

Sleep, pericyte subtypes and cognitive decline in adults with and without Alzheimer's disease.

Brain : a journal of neurology pii:8189044 [Epub ahead of print].

Sleep fragmentation is common in older adults and is associated with cognitive impairment and dementia, as well as key histopathological correlates of dementia, including small vessel disease and cerebral infarcts. Vascular and blood-brain barrier dysfunction are thought to contribute to cognitive decline and dementia. Pericytes, a key vascular cell type, may play a key role. In model organisms, sleep disruption is associated with pericyte dysfunction and blood-brain barrier breakdown. Recent advances in single-nucleus RNA sequencing (snRNAseq) technology have identified two transcriptionally distinct subtypes of pericytes: extracellular matrix protein-expressing M-pericytes and solute carrier-expressing T-pericytes. However, the relationship between sleep, pericyte biology and cognition in humans remains unclear. We tested the hypothesis that differences in the composition of brain pericyte subpopulations, as inferred from marker gene expression, may link sleep fragmentation and cognitive decline. We leveraged two published human brain snRNAseq datasets to identify specific marker genes for M- and T-type pericytes. We then used post-mortem bulk RNAseq data from the dorsolateral prefrontal cortex (n = 1092) and lateral orbitofrontal cortex (n = 495) to quantify expression of these marker genes in older adults in two longitudinal cohort studies: the Religious Orders Study and Rush Memory and Aging Project. We derived trajectories of global cognitive function from participants' ante-mortem annual cognitive assessments, while sleep fragmentation was derived from ante-mortem wrist-actigraphy recordings from a subset of 572 participants. We used multivariate linear regression to relate pericyte marker gene expression to sleep fragmentation and cognitive decline in the decade preceding death. In the dorsolateral prefrontal cortex, greater average sleep fragmentation was associated with greater expression of M-pericyte marker genes [estimate = +3.65 × 10-1, standard error (SE) = 1.61 × 10-1, P = 0.024] but not T-pericyte marker genes. Dorsolateral prefrontal cortex expression of M-pericyte (estimate = -8.30 × 10-3, SE = 3.37 × 10-3, P = 0.014) but not T-pericyte marker genes was associated with more rapid cognitive decline in the 10 years prior to death. In the lateral orbitofrontal cortex, greater sleep fragmentation was also associated with greater composite M-pericyte gene expression (estimate = + 4.48 × 10-1, SE = 1.92 × 10-1, P = 0.02), which in turn was associated with faster cognitive decline in the decade preceding death (estimate = -1.30 × 10-2, SE = 4.55 × 10-3, P = 0.0044). These findings identify a potential role of M-pericytes in linking sleep fragmentation and cognitive trajectories in older adults. Additionally, our findings highlight the importance of vascular mechanisms in linking disrupted sleep to dementia.

RevDate: 2025-07-14

Bi S, Liu S, Zhu K, et al (2025)

Preclinical and experimental evidence of salvianolic acid B in the treatment of neurological diseases.

Frontiers in pharmacology, 16:1606146.

BACKGROUND: Neurological diseases such as stroke and Alzheimer's disease pose increasing challenges to global public health. Salvianolic Acid B (SalB), a major active component of Salvia miltiorrhiza, has garnered attention due to its anti-inflammatory, antioxidant, neuroprotective, and pro-angiogenic properties in neurological disease treatment.

PURPOSE: This paper aims to review the mechanisms and effects of SalB in the treatment of neurological diseases, exploring its role in improving neurological function, mitigating neuroinflammation, and reducing oxidative stress.

RESULTS: SalB demonstrates multifaceted mechanisms in neurological disease management. In animal models of cerebral ischemia/reperfusion injury, SalB reduces infarct size and enhances neurological recovery via anti-inflammatory, anti-oxidative stress, and angiogenic pathways. It protects the blood-brain barrier and inhibits neuronal apoptosis in stroke models. In spinal cord injury models, SalB alleviates edema and promotes motor function recovery. In Alzheimer's disease models, SalB suppresses amyloid-beta formation and neuroinflammation. Additionally, SalB exhibits antidepressant and analgesic effects in pain-depression comorbidity models. These effects are mediated through the regulation of signaling pathways, including NF-κB, AMPK, PI3K/Akt, and Nrf2, highlighting SalB's broad therapeutic potential in neurological diseases.

CONCLUSION: SalB exhibits promising prospects in the treatment of neurological diseases. However, its clinical application faces challenges such as chemical stability and bioavailability. Further research on the mechanisms of SalB and innovative drug delivery strategies is needed to advance its application in neurological disease therapy.

RevDate: 2025-07-14

Wu W, Meng T, Han L, et al (2025)

Bridging traditional Chinese medicine and Alzheimer's disease: the pivotal role of gut microbiota in multitarget therapeutic mechanisms.

Frontiers in pharmacology, 16:1630205.

Microbiota-gut-brain axis communication represents another crucial pathway in the pathogenesis of Alzheimer's disease (AD), whereby gut microbiota significantly impacts AD pathology by modulating immune, metabolic, digestive, and neurological functions. Although research on treating AD through gut microbiota interventions is advancing, substantial breakthroughs remain limited. Given AD's complex pathological mechanisms, Traditional Chinese Medicine (TCM) presents a clear advantage with its multi-target effects. During the processes of TCM intake, absorption, and therapeutic action, the gut microbiota serves both as a mediator and as a therapeutic target. However, the mechanisms by which TCM interacts with gut microbiota to exert beneficial effects on AD remain largely unclarified. Here, we review the mechanisms through which TCM may intervene in AD from the perspective of gut microbiota, examining the potential mechanisms and clinical application prospects of Chinese herbal medicine in regulating the gut microbiome. This provides a novel theoretical foundation and methodological support for further research into herbal therapies for AD.

RevDate: 2025-07-14

Tang SL, Subramaniam P, Siau CS, et al (2025)

Risk factors of mild behavioral impairment: a systematic review.

Frontiers in psychology, 16:1586418.

INTRODUCTION: Mild Behavioral Impairment (MBI) represents a predementia syndrome marked by neuropsychiatric symptoms that may precede detectable cognitive decline. Identifying factors associated with MBI is critical for developing targeted prevention strategies in neurodegenerative disorders.

METHODS: This systematic review adhered to PRISMA 2020 guidelines, searching PubMed, Scopus, Web of Science, ScienceDirect, and Embase through May 2024. Forty-one human studies meeting predefined inclusion criteria were selected through dual independent screening.

RESULTS: Five key domains emerged: (1) Genetic susceptibility (APOE ε4 allele showing strongest association), (2) Motor system pathology (particularly Parkinsonian features), (3) Multisensory deficits (auditory impairment demonstrating bidirectional relationships), (4) Metabolic dysregulation (diabetes mellitus and frailty phenotypes), and (5) Neuroanatomical correlates (frontolimbic atrophy patterns on MRI). The interaction between genetic predisposition and environmental/lifestyle factors appears central to MBI pathogenesis.

CONCLUSION: MBI manifests as a multidimensional interface between molecular mechanisms and clinical phenomenology. Our synthesis supports the implementation of transdiagnostic screening protocols integrating behavioral biomarkers with conventional cognitive assessments. Future research should prioritize longitudinal designs to establish causal pathways and intervention thresholds.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Dong Q, Sheng Y, Zhu J, et al (2025)

MRI-Driven Longitudinal Studies of Hippocampal Alterations During the Initial Cognitive Decline.

IEEE journal of translational engineering in health and medicine, 13:98-110.

Based on available magnetic resonance imaging (MRI) studies, hippocampal alteration is one of the hallmarks during cognitive decline. However, the longitudinal hippocampal morphometric changes during the initial cognitive decline are unclear. Exploring a validated biomarker with high clinical relevance is urgent. This work proposed an automated MRI-driven longitudinal hippocampal alteration analysis system (LHAAS), which consists of hippocampal segmentation, reconstruction, registration, multivariate morphometric feature extraction, and longitudinal analysis of hippocampal morphometric and volumetric differences between groups. LHAAS was applied on two groups: cognitive unimpaired (CU) participants who maintained cognitive unimpaired (non-Progressors), and participants who converted to MCI during the following four years (Progressors). LHAAS can detect and visualize subtle deformations in the bilateral hippocampus of CU progressors four years before they show initial cognitive decline. For CU progressors, hippocampal atrophy initially occurs at the CA1 subregion and then along with disease progression, spreading to the CA2-3 and Subiculum subregion, exhibiting a left-greater-than-right trend. The volumetric analyses showed similar results. Besides, hippocampal subregions highly correlated with clinical measurement were identified by correlation analysis. LHAAS can accurately reflect the small hippocampal subregional atrophy at preclinical AD. This proposed system can track the longitudinal hippocampal alterations in the early stages of AD and provide insights for early intervention. Clinical and Translational Impact Statement: LHAAS offers early detection of subtle hippocampal alterations at preclinical AD. This advance enables pathological research and timely interventions to potentially improve patient outcomes in clinical implementation.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Perez F, Morisaki J, Kanakri H, et al (2025)

A Novel Design of a Portable Birdcage via Meander Line Antenna (MLA) to Lower Beta Amyloid (Aβ) in Alzheimer's Disease.

IEEE journal of translational engineering in health and medicine, 13:158-173.

Late Onset Alzheimer's Disease (LOAD) is the most common cause of dementia, characterized by the deposition of plaques primarily of neurotoxic amyloid-[Formula: see text] ([Formula: see text]) peptide and tau protein. Our objective is to develop a noninvasive therapy to decrease the toxic A[Formula: see text] levels, using repeated electromagnetic field stimulation (REMFS) in the brain of Alzheimer's disease patients. We previously examined the effects of REMFS on [Formula: see text] levels in primary human brain (PHB) cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro (DIV7) treated with 64 MHz with a SAR of 0.6 W/Kg, one hour daily for 14 days (DIV 21) had significantly reduced (p =0.001) levels of secreted [Formula: see text]-42 and [Formula: see text]-40 peptide without evidence of toxicity. The EMF frequency and power, and SAR levels used in our work is utilized in MRI's, thus suggesting REMFS can be further developed in clinical settings to lower ([Formula: see text]) levels and improve the memory in AD patients. These findings and numerous studies in rodent AD models prompted us to design a portable RF device, appropriate for human use, that will deliver a homogeneous RF power deposition with a SAR value of 0.4-0.9 W/kg to all human brain memory areas, lower ([Formula: see text]) levels, and potentially improve memory in human AD patients.The research took place at the Indiana University School of Medicine (IUSM) and Purdue University Indianapolis. The first phase was done in PHB cultures at the IUSM. Through this phase, we found that a 64 MHz frequency and an RF power deposition with a SAR of 0.4-0.6 W/kg reduced the (A[Formula: see text]) levels potentially impacting Alzheimer's disease. The second phase of the project was conducted at Purdue University, we used ANSYS HFSS (High Frequency Simulation System) to design the devices that produced an appropriate penetration depth, polarization, and power deposition with a SAR of 0.4-0.9 W/kg to all memory brain areas of several numerical models. In Phase II-B will validate the device in a physical phantom. Phase III will require the FDA approval and application in clinical trials.The research parameters were translated into a designed product that fits comfortably in human head and fed from an external RF source that generates an RF power deposition with a SAR of 0.4-0.9 W/kg to a realistic numerical brain. The engineering design is flexible by varying the leg capacitors of the Meander Line Antenna (MLA) devices. Thermal outcomes of the results guarantee less than 0.5 C temperature increase within one-hour time of exposure, which can be used in clinical trials for AD patients. Design parameters include dimension of the coil, the MLA structure, conducting material, and capacitance values with the produced EM fields. The flexible design was achieved by varying the additive capacitance between conductors, and via a hybrid approach integrating a birdcage with sixteen MLA. A coil antenna size within 16 cm radius and 13 cm length was achieved. A capacitance between 6.9 nF and 9.2 nF were observed when copper materials with 16 conductors were used to achieve the research parameters in focus.The medical project proposed here has three phases: The initial phase of determining the research parameters for reducing A[Formula: see text] levels in human brain cultures and animal studies was completed at the IUSM. The translational engineering design of the REMS device and the numerical head and Antenna devices was successfully completed and presented in this paper by Purdue University and IUSM. Future phases will require manufacture and experimental validation of the REMS device with FDA approval for human application. Clinical impact: Our biological studies in human brain cultures showed that an RF power with a SAR of 0.4-0.9 W/kg at 64 MHz, lowered A[Formula: see text] levels, which potentially will prevent the death of the brain neurons and improve memory in AD. The fact that we found a safe RF power deposition with a SAR value associated with the proposed biological effects in human neurons and that 64 MHz provides a penetration depth of 13.5 cm that reaches all memory areas in a human brain makes the design and manufacture of this device of high clinical impact in the study of these exposures on the treatment of Alzheimer's and other protein associate diseases. Also, 64 MHz and RF power deposition with similar SAR levels are administer routinely in routine MRI for more than 4 decades makes it a safe framework for these novel therapeutic strategy.Clinical and Translational Impact Statement: The basic science work presented previously is both mechanistic and translational, and would advance the field of neuroscience as well as AD. This prompted us to joint efforts between the Indiana University School of Medicine and the electrical and computer engineering at Purdue University to design and develop a suitable EMF device for human treatments. Recently, our engineering team designed a birdcage antenna that generate a homogeneous RF power deposition with the same SAR values of our biological experiments in a realistic numerical human brain. Here, the engineering research has been extended to investigate the design of a portable flexible birdcage antenna that will enable adjustments to fit physical patient's characteristics, such as geometry, head size, and tissue dimensions. This new device is expected to improve SAR uniformity and may reduce the likelihood of untreated regions in the brains of patients during treatments. Also, here we determined that the maximum temperature rise of these exposures was less than 0.5°C, which is a safe level per regulatory agencies. This study considers a portable device system that will achieve the research parameters and patient satisfaction regarding reliability and comfort.

RevDate: 2025-07-14

Jan MT, Furht B, Moshfeghi S, et al (2025)

Enhancing road safety: In-vehicle sensor analysis of cognitive impairment in older drivers.

Multimedia tools and applications, 84(17):18711-18732.

With the ongoing expansion of the aging population, it is increasingly critical to prioritize the safety of older drivers. The objective of this study is to utilize sensor data in order to detect early indications of impairment, thereby facilitating proactive interventions and enhancing road safety for the elderly. This article provides an overview of the research approach, presents significant results, and analyzes the consequences of utilizing in-vehicle sensors i.e. vision and telematics, to mitigate cognitive decline among elderly drivers; in doing so, it promotes progress in the domains of public health and transportation safety by standardizing the use of such devices to automatically assess the drivers' cognitive functions.

RevDate: 2025-07-14

Prabha S, Choudhury A, Jawaid T, et al (2025)

Multi-targeted approach via apigenin-7-O-glucoside for therapeutic intervention of Tau phosphorylating kinases in Alzheimer's disease.

3 Biotech, 15(8):252.

UNLABELLED: Alzheimer's disease (AD) is one of the leading tauopathies in which several kinases phosphorylate Tau in response to Aβ oligomers, inflammation, calcium dysregulation, oxidative stress, mitochondrial dysfunction, or disruption of the key signaling pathways. Tau is phosphorylated by Ser/Thr kinases such as GSK3β, CDK5, MAPK14, and MARK2, as well as Tyr kinases like Fyn. Given the large crosstalk among these kinases, targeting one of these kinases is ineffective in treating tauopathies such as AD, highlighting the need for a multi-targeted approach. In this study, we targeted key kinases involved in Tau hyperphosphorylation using compounds derived from the medicinal plant Berberis lycium (B.ly.), which is reported to have anti-inflammatory, autophagy, and antioxidant properties. We employed virtual screening, ADMET evaluation, PASS analysis, DFT, molecular dynamics (MD) simulation, and MM/PBSA studies to assess the interaction of B.ly. compounds with CDK5, Fyn, GSK3β, MARK2, and MAPK14. Apigenin-7-O-glucoside (A7OG) was selected for its strong binding affinity within the ATP-binding pockets of these kinases. MD simulations demonstrated that A7OG exhibited promising inhibitory effects on CDK5, Fyn, MARK2, and MAPK14, with minimal fluctuation in its interaction with GSK3β. MM/PBSA analyses indicated stable binding energies for all the kinase-A7OG complexes. Our multitargeted investigations revealed that A7OG could be a promising molecule implicated in modulating tau hyperphosphorylating kinases that could lead to the development of therapeutic interventions in AD treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04413-3.

RevDate: 2025-07-14

Kane JPM, Fitzpatrick RL, Betzhold S, et al (2025)

A common outcome set for trials in dementia with Lewy bodies (DLB COS).

Alzheimer's & dementia (New York, N. Y.), 11(3):e70134.

INTRODUCTION: Methodological heterogeneity in dementia with Lewy bodies (DLB) trials contributes to publication bias and makes evidence synthesis and meta-analysis challenging. We aimed to develop a core outcome set for DLB (DLB COS) trials to improve consistency and comparability in DLB research.

METHODS: We conducted a systematic review to identify outcomes and administered a two-stage Delphi survey to a diverse panel of lay and professional stakeholders. We asked respondents which outcomes should be prioritized and included in DLB COS.

RESULTS: Forty-nine outcomes were presented to survey respondents. Consensus was reached regarding eight outcomes for the final DLB COS: delusions/paranoia; fluctuations in cognition, attention, and arousal; functioning; global cognition; hallucinations; quality of life; motor parkinsonism; and rapid eye movement sleep behavior disorder.

DISCUSSION: If adopted, DLB COS can enhance the comparability of research findings and facilitate standardization and harmonization.

HIGHLIGHTS: A systematic review revealed heterogeneity in dementia with Lewy bodies (DLB) study outcomes.Our study produced a DLB Core Outcome Set (DLB COS) comprising eight outcomes.DLB COS sets the minimum reporting standards for future trials.DLB-specific rating scales incorporating these outcomes are needed.Addressing this gap is a strategic priority in DLB research.

RevDate: 2025-07-14

Langhough RE, Norton DL, Cody KA, et al (2025)

Use of preclinical Alzheimer's disease trajectories for clinical trial design.

medRxiv : the preprint server for health sciences pii:2025.05.01.25326668.

INTRODUCTION: This study uses longitudinal amyloid biomarker and cognitive data to generate sample size estimates for two-armed, pre-clinical amyloid clearance clinical trials.

METHODS: PET PiB DVR ranges defined three amyloid groups (positive, "A+"; sub threshold/low positive, "subA+"; and negative, "A-") in cognitively unimpaired Wisconsin Registry for Alzheimer's Prevention participants. Amyloid group trajectories estimated from mixed effects models informed per-treatment-arm sample size estimates to detect plausible treatment effects over 3-year (biomarker) or 6-year (cognition) study windows (80% power).

RESULTS: To detect ≥60% slowing in PiB accumulation, ≤40 may be needed per arm for both SubA+ and A+; to detect the same effect sizes in plasma p-tau217 trajectories, ∼50-1700 are needed, depending on assay and amyloid subgroup. Among cognitive outcomes, Digit Symbol Substitution and a 5-test Preclinical Alzheimer's Cognitive Composite consistently required fewest (<2000) per arm.

DISCUSSION: Early intervention study planning will benefit from selection of outcomes that are most sensitive to AD biomarker-related preclinical change.

RevDate: 2025-07-14

Chandrasekar SK, Arthanari J, Chandrasekar KK, et al (2025)

Advanced Imaging Techniques (PET, fMRI, DTI) in Early Detection of Neurodegenerative Diseases: A Systematic Review.

Health science reports, 8(7):e70855.

BACKGROUND: Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and vascular and frontotemporal dementia (FTD), are characterized by progressive cognitive and motor decline. So, timely detection, especially early in the disease process, is crucial. Positron Emission Tomography (PET), Functional Magnetic Resonance Imaging (fMRI), and Diffusion Tensor Imaging (DTI) are advanced neuroimaging techniques that have shown promise for early diagnosis.

OBJECTIVE: This review evaluates the diagnostic accuracy and clinical utility of PET, fMRI, and DTI in the early detection of neurodegenerative diseases.

METHODS: A systematic search was conducted using PubMed, Google Scholar, and Cochrane Library for studies published between 2014 and 2024. Inclusion criteria focused on phase 2 and 3 clinical trials involving adult patients with AD, PD, and FTD. Studies were assessed for diagnostic accuracy, sensitivity, specificity, and identification of early biomarkers using PET, fMRI, and DTI. Data were extracted and analyzed from 14 selected studies.

RESULTS: PET imaging with tracers like 18F-flortaucipir provided visualization of amyloid and tau aggregates in AD and dopaminergic changes in PD. PET showed a strong association with amyloid and tau pathology in AD, with up to 95% diagnostic performance. Another useful technique in identifying early changes in the brain networks was resting-state fMRI (rs-fMRI), with a diagnostic accuracy of 80%-95%. DTI offered essential data on white matter connectivity and showed microstructural alterations that pointed to early neurodegenerative processes. Integrating these neuroimaging modalities with machine learning models further enhanced diagnostic accuracy.

CONCLUSION: PET, fMRI, and DTI are valuable tools for the early diagnosis of neurodegenerative diseases. These techniques can identify structural and functional changes in the brain before the onset of clinical signs. Integrating these imaging techniques with machine learning improves diagnostic outcomes. Further large-scale studies with standardized methodologies are needed to validate these findings and implement these techniques in clinical practice.

RevDate: 2025-07-14

Zhao T, Pan P, Zhou Y, et al (2025)

Age-sex differences in Alzheimer's and related dementias burden and risk factors in east and Southeast Asia: results from the 2021 GBD study.

Frontiers in aging neuroscience, 17:1562148.

BACKGROUND: Alzheimer's disease and related dementias (ADRD) significant global public health challenges, leading to severe disability in patients and placing a heavy burden on caregivers. However, epidemiological studies focusing on ADRD in specific regions remain limited. This study aims to comprehensively analyze and describe the current status and changing trends of ADRD in Non-High-income East Asia (NHIEA), Non-High-income Southeast Asia (NHISEA), and High-income Asia Pacific (HIAP), providing more detailed real-world data to inform policymaking.

METHODS: The data for ADRD used in this study were extracted from the 2021 Global Burden of Disease (GBD) database. We employed three major indicators of disease burden-prevalence, incidence, and years lived with disability (YLD)-and explored associated risk factors, further analyzing trends by age and sex. The results are presented as mean values with 95% uncertainty intervals (UIs). Additionally, we explored the differences between NHIEA, NHISEA, HIAP and other regions, as well as the potential associations between the disease burden of Alzheimer's and other dementias and socioeconomic factors.

RESULTS: The findings indicate that the burden of dementia is rising in East and Southeast Asia, with women showing a higher burden across all indicators. Notably, in NHIEA, particularly in China, the burden of dementia has increased with the rising Social Demographic Index (SDI). China experienced a 27.3% increase in Alzheimer's disease and other dementia ASYRs from 1990 to 2021, with a sharp 7.6% annual surge in 2021 alone, outpacing regional averages. Gender analysis revealed that women bear a disproportionate burden of Alzheimer's disease and related dementias, especially after menopause, when the risk increases significantly. The study also identified smoking, high blood sugar, and high body mass index as important risk factors affecting the disease burden. The contribution of these risk factors varies across regions, genders, and age groups.

CONCLUSION: The health burden of ADRD remains substantial, with distinct patterns observed across NHIEA, NHISEA, and HIAP, including regional variations in gender, age, and risk factors. These findings highlight the need for tailored approaches to allocate healthcare resources and implement appropriate control measures based on the specific conditions of each region to address this growing public health challenge. Future research should prioritize comparative analyses across continents and within regions to inform the development of more region-specific prevention strategies for ADRD.

RevDate: 2025-07-14

Silva Franco L, Rodrigues DA, Baumart GJ, et al (2025)

Drug Repurposing by Virtual Screening: Identification of New Already Approved ROCK Inhibitors as Promising Drugs to Target Neurodegeneration.

ACS omega, 10(26):28446-28465.

ROCK kinases are key players in neurodegenerative diseases such as Alzheimer's disease (AD), making them attractive therapeutic targets. In this study, we developed a pharmacophoric map of ROCK inhibitors and highlighted the key affinity sites in ROCK1/2 through molecular modeling. Virtual screening led to the identification of six approved drugs as ROCK inhibitors: ruxolitinib (36), baricitinib (37), ponatinib (38), tivozanib (39), nialamide (40), and tucatinib (41). Ruxolitinib (36) (hROCK1 IC50 = 0.025 μM; hROCK2 IC50 = 0.007 μM) and baricitinib (37) (hROCK1 IC50 = 0.019 μM; hROCK2 IC50 = 0.011 μM) showed the highest potency, while tivozanib (39) displayed 15-fold selectivity for ROCK2 over ROCK1. Molecular dynamics revealed that ruxolitinib (36) forms stable bidentate hydrogen bonds with the ROCK hinge region and has selectivity across the AGC kinase family. Biological assays confirmed ruxolitinib's (36) safety in neuronal and glial cells and its ability to reduce C3 immunolabeling, a glial inflammation marker, in LPS-treated astrocytes. These findings not only highlight ruxolitinib (36) as a promising candidate for AD but also provide a structural basis for designing novel dual JAK-ROCK inhibitors and pave the way for further in vitro and in vivo studies. Moreover, the validated pharmacophoric map for ROCK inhibition highlights the identification of an affinity pocket that can be useful for the design of new ROCK inhibitors.

RevDate: 2025-07-14

Valle-Jiménez X, Osorio-Paz I, S Alavez (2025)

Phenolic Acids Commonly Found in Natural Products Modulate Protein Aggregation in Caenorhabditis elegans Neurodegeneration Models.

ACS omega, 10(26):27861-27868.

Abnormal protein accumulation is frequently associated with the gradual degeneration of the central nervous system, which results in the development and progression of several neurodegenerative diseases (NDs). Since the incidence of ND is on the rise, their effects represent a substantial psychological and economic burden. As we advance in understanding human aging mechanisms, it is desirable to accelerate the discovery of molecules that can modulate human aging and perhaps postpone the onset of age-related disease. Therefore, uncovering compounds that can prevent the formation of protein aggregates should be a priority in the aging research field. Phenolic acids are organic compounds found in many natural products, such as vegetables and fruits. These compounds have been shown to have potential neuroprotective benefits. However, its effects on protein aggregation related to neurodegeneration processes are still not clear. In this study, we thoroughly explored the ability of four phenolic acids: caffeic (CA), p-coumaric (p-CoA), ferulic (FA), and gallic (GA) acids to prevent protein aggregation in three models of human neurodegeneration, such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. We found that high CA, p-CoA, FA, and GA concentrations reduce the β-amyloid-aggregation-induced paralysis phenotype by up to 32%. Also, high CA, FA, and GA concentrations decreased paralysis percentage and polyQ aggregations by 25, 26, and 47%, respectively. Interestingly, high concentrations of p-CoA reduced polyQ aggregation but not the percentage of protein aggregation-induced paralysis. Additionally, only high concentrations of CA, along with lower concentrations of FA and GA, demonstrated the potential to reduce α-synuclein aggregation. Our findings suggest that CA, FA, and GA are worthy candidates for acting as neuroprotectors in mammals.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Macedo ADES, Ferreira TM, Krejcová LV, et al (2025)

Neuroprotective effects of essential oils in animal models of Alzheimer's and Parkinson's disease: a systematic review.

PeerJ, 13:e19643.

Essential oils (EOs), derived from aromatic plants, have garnered significant attention for their potential neuroprotective properties in neurodegenerative diseases. This systematic review evaluates recent advancements in understanding the neuroprotective role of EOs against Alzheimer's disease (AD) and Parkinson's disease (PD). Following PRISMA guidelines, we conducted a comprehensive literature search across three major databases (PubMed, Virtual Health Library, and Web of Science) from inception to January 2024, resulting in thirteen high-quality in vivo studies for qualitative analysis. The review assessed various EOs, with hydrodistillation being the predominant extraction method (66.66% of studies). Studies primarily utilized Wistar rats (46.15%) and various mouse strains, employing diverse disease induction methods including β-amyloid administration (30.7% of AD models), rotenone (7.7% of PD models), and 6-hydroxydopamine (7.7% of PD models). Administration routes varied, with oral administration being most common (38.4%), with gavage and inhalation each accounting for 23.1% of studies. Key findings revealed that EOs exhibit multifaceted neuroprotective mechanisms. In AD models (69.3% of studies), EOs reduced oxidative stress markers, decreased pro-inflammatory cytokine levels, and increased neuroprotective protein expression. In PD models (30.7% of studies), EOs demonstrated significant dopaminergic neuroprotection, with improvements in behavioral outcomes. Behavioral assessments showed consistent enhancements in memory, learning, and motor functions across studies. The systematic analysis provides compelling evidence for EOs' neuroprotective efficacy, particularly in early-stage intervention. However, limitations include the predominance of animal studies, variability in dosing, and administration methods. The most promising EOs identified were from Pinus halepensis, Citrus limon, and Acorus species, showing particular efficacy in reducing cognitive deficits and oxidative stress. Chemical analysis revealed that compounds such as α-pinene, limonene, and β-caryophyllene were predominantly responsible for the observed therapeutic effects. The molecular mechanisms underlying these effects included modulation of cholinergic transmission, reduction of amyloid-β aggregation, and enhancement of antioxidant enzyme activities. These findings suggest that EOs could serve as valuable complementary therapeutic agents, particularly when standardized for specific bioactive compounds. Future research should focus on standardizing EO compositions, conducting human clinical trials to establish safety and efficacy profiles, and investigating potential synergistic effects with conventional treatments.

RevDate: 2025-07-14

Siciliano B, Henkel ND, Ryan V WG, et al (2025)

Proinflammatory transcriptomic and kinomic alterations in astrocytes derived from patients with familial Alzheimer's disease.

Brain, behavior, & immunity - health, 47:101044.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by profound neuronal and cognitive decline, with increasing evidence implicating astrocyte dysfunction in disease pathology. While traditional therapeutic approaches have primarily targeted neurons, the crucial role of astrocytes in metabolism, neurotransmission, amyloid-beta clearance, and neuroinflammation underscores their potential as therapeutic targets. In this study, we employed a multiomic integrative analysis combining transcriptomic and kinomic profiling of human induced pluripotent stem cell (hiPSC)-derived astrocytes from patients with familial AD (fAD) compared to healthy controls (HCs). Our transcriptomic analysis identified 1249 significantly differentially expressed genes, highlighting a pronounced upregulation of inflammatory genes (SERPINA3, IL6R, IL1RAP, TNFRSF11A) and a concomitant downregulation of genes essential for synaptic support and ion channel function (STMN2, NMNAT2, SCN2A, GRIN1). Kinomic profiling revealed dysregulated kinase activities within DYRK, GSK, and MAPK families, further implicating altered kinase signaling pathways in astrocyte dysfunction. Integration of these datasets pinpointed critical molecular hubs, notably within the PI3K signaling and inflammatory pathways, highlighting targets such as JAK2, STAT3, and AKT1 as potential modulators of disease progression. Furthermore, leveraging the Library of Integrated Network-Based Cellular Signatures (LINCS) platform, we identified chemical perturbagens, including fluticasone propionate and Akt inhibitors, capable of reversing the transcriptomic signatures associated with fAD astrocytes. This integrative multiomic approach not only enhances our understanding of astrocyte-specific molecular mechanisms in AD but also provides novel targets for therapeutic intervention aimed at mitigating astrocyte-driven neurodegeneration.

RevDate: 2025-07-14

Ohara H, Yamanaka M, Inoue K, et al (2025)

Case Report: Role of hypoglycemia in seizure aggravation in a case of focal epilepsy: revealing a missing link between diabetes and dementia.

Frontiers in neuroscience, 19:1604552.

AIM: While low-frequency electroencephalographic (EEG) activity increases during hypoglycemia, the relationship between hypoglycemia and changes in epileptic activities has not been fully investigated. Recently, the American Clinical Neurophysiology Society's EEG Terminology 2021 defined criteria for Brief Potentially Ictal Rhythmic Discharges (BIRDs) including rhythmic fast activities. We evaluated the association between hypoglycemia and BIRDs.

METHODS: Data from a 27-year-old female with focal epilepsy and idiopathic hypoglycemia, who underwent scalp-recorded long-term video-EEG using the International 10-20 system with T1/T2 electrodes, were analyzed. Her anti-neuronal antibody test results were negative. EEG recordings over 6 h were retrospectively evaluated in longitudinal bipolar montages at 15 s per display screen. The number and duration of BIRDs were assessed in each 30 min epoch. Glucose levels were obtained using a flash glucose monitoring system, and the average glucose level for each epoch was calculated using the area under the curve (AUC), measured by pixel-counting software. The relationship between the number and duration of BIRD subtypes and average glucose levels was evaluated using cut-off values of 70, 60, and 50 mg/dL.

RESULTS: During the recording, the EEG showed focal slow activities, epileptic spikes, and BIRDs in the left temporal area, but no clinical or electrographic seizures were observed. The number of evolving BIRDs per epoch was significantly higher during more severe hypoglycemia when the cut-off values were set at 60 mg/dL (2.00 ± 0.71 vs. 0.38 ± 0.70, mean ± SD, p < 0.05, Mann-Whitney U test) and 50 mg/dL (2.33 ± 0.47 vs. 0.44 ± 0.68, p < 0.05). The total duration of definite BIRDs per epoch also showed a statistically significant difference when the cut-off was set at 50 mg/dL (3.15 ± 1.82 vs. 2.10 ± 1.00 s, p < 0.05).

CONCLUSION: Maintaining glucose levels above 60 mg/dL appears important for the early termination of epileptic rhythmic discharges. Individuals with diabetes are at high risk of Alzheimer's disease (AD), and hippocampal hyperactivity contributes to epileptic seizures, amyloid deposition, and disease progression. Fluctuations in blood glucose levels, including episodes of hypoglycemia, increase the risk of dementia. The present findings suggest a potential causative role of hypoglycemia in AD and propose a precise method to correlate glucose levels with brain activities.

RevDate: 2025-07-14

Rohatgi S, Ford JN, Zhu S, et al (2025)

Correlation of White Matter Hyperintensities and Perivascular Spaces With Montreal Cognitive Assessment (MoCA) Scores in Patients Evaluated for Anti-amyloid Therapy.

Cureus, 17(6):e85832.

Objective This study aimed to investigate the relationship between white matter hyperintensities (WMH) and perivascular spaces (PVS) on magnetic resonance imaging (MRI) with Montreal Cognitive Assessment (MoCA) scores in patients referred for possible lecanemab therapy based on clinical suspicion of Alzheimer's disease (AD) prior to biomarker confirmation. Materials and methods In this retrospective review, 149 consecutive patients with suspected AD between November 2023 and June 2024 who were evaluated for possible lecanemab therapy were identified. All underwent brain MRI and had valid MoCA scores. WMH were graded using the Fazekas scale (0-3). PVS were visually graded (1-4) in the basal ganglia and centrum semiovale on T2-weighted images. Generalized linear models assessed the association between imaging markers and MoCA, adjusting for age, sex, hypertension (HTN), hyperlipidemia (HLD), and diabetes mellitus (DM). Results The mean MoCA score was 19.56, reflecting mild to moderate cognitive impairment. The mean Fazekas score was 1.37, indicating mild to moderate WMH burden, while the mean PVS scores for basal ganglia and centrum semiovale were 1.99 and 2.37, respectively. There is no significant correlation between age and MoCA scores in our patient population. A negative association of -0.1 between the Fazekas score and MoCA score was observed after controlling for the effects of PVS. In contrast, PVS did not significantly correlate with MoCA score. Conclusion In patients evaluated for possible lecanemab therapy, a higher WMH burden was negatively associated with global cognition, whereas PVS demonstrated no significant relationship with MoCA scores. These findings suggest that WMH may be an imaging marker of vascular pathology in those suspected of AD.

RevDate: 2025-07-14

Koya PC, Kolla SC, Madala V, et al (2025)

Potential of Nerve Growth Factor (NGF)- and Brain-Derived Neurotrophic Factor (BDNF)-Targeted Gene Therapy for Alzheimer's Disease: A Narrative Review.

Cureus, 17(6):e85814.

Alzheimer's disease (AD) involves progressive degeneration of cholinergic and synaptic networks, leading to cognitive decline. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), essential for neuronal survival and plasticity, have gained therapeutic interest. Particularly through gene therapy approaches. Preclinical studies have shown improved neuronal integrity and memory restoration. Nonetheless, clinical translation faces significant challenges, including invasive delivery, vector limitations, and receptor dysregulation. Gene therapy must be focused on precision-targeted, minimally invasive delivery systems, controlled gene expression, and early-stage intervention. This review critically evaluates NGF- and BDNF-based gene therapies, highlighting advances, limitations, and future directions that may position neurotrophin modulation as a viable disease-modifying strategy in AD.

RevDate: 2025-07-14

Katsipis G, Tzekaki EE, Andreadou EG, et al (2024)

The effect of physical exercise with cognitive training on inflammation and Alzheimer's disease biomarkers of Mild Cognitive Impairment patients.

Neuroscience applied.., 3:104085.

Physical exercise (PE) was proven crucial for cognitive health of both demented and cognitively intact individuals. Simultaneous cognitive training may augment PE beneficial effects in demented patients. However, it is still debatable how PE and/or cognitive training reflect on mild cognitive impairment (MCI) and pathological factors related to Alzheimer's disease, namely inflammatory cytokines interleukin (IL) 1 beta and 6, tumor necrosis factor alpha (TNF-α), amyloid beta (Αβ) peptides, total tau protein (t-tau) and tau phosphorylated at threonine 181 (p-tau181). In the current study, 74 MCI patients were allocated to three groups: non-intervention (Control), PE, and PE with cognitive training (Mixed). Blood serum was received at the Baseline and after the intervention (at 3 months). Levels of IL-1β, IL-6, TNF-α, Αβ42, Αβ40, tau and p-tau181 were determined with enzyme-linked immunosorbent assay. PE and Mixed interventions reduced the levels of IL-1β, IL-6 and of p-tau181. Augmented levels of Αβ42 and the ratio Αβ42/40, and reduced ratio p-tau181/Αβ42 were verified only in the PE group. Reduced levels of TNF-α, Αβ40 and t-tau were verified only at the Mixed group. In addition, correlation analyses provided a significant interrelation between the alleviation of inflammation and p-tau181/Αβ42 reduction in patients of the Mixed intervention. These results suggest the beneficiary effect of PE and cognitive training on the regulation of inflammation resulting in mitigation of AD-related blood biomarkers and urge for their employment as non-pharmacological alternatives for stalling the progression of dementia.

RevDate: 2025-07-14

Tang Q, Xu W, Zhang F, et al (2025)

Interdisciplinary research on periodontitis and depression: a bibliometric analysis of research trends, hotspots and future directions.

Frontiers in oral health, 6:1588737.

BACKGROUND: Periodontitis, a chronic inflammatory disease affecting nearly 50% of the global population, has been increasingly linked to depression, a prevalent psychiatric disorder.

METHODS: This study conducted a comprehensive bibliometric analysis to explore the association between periodontitis and depression, from 2000 to 2024 via the Web of Science Core Collection (WoSCC) database. Bibliometric parameters were extracted and bibliometric analysis was conducted via VOSviewer, and CiteSpace software.

RESULTS: A total of 205 publications, comprising 173 original articles and 32 reviews, were analyzed via VOSviewer and CiteSpace, with a focus on countries, institutions, authors, journals, keywords, and citations. The results revealed a significant increase in publications, with notable contributions from China, the USA, and Brazil, accounting for 43.9% of all studies. The collaborative networks highlight the growing interdisciplinary nature of this field. "Depression" (n = 71), "disease" (n = 66), "association" (n = 50), "oral health" (n = 47) and "stress" (n = 37) were the most frequent keywords, reflecting current research hotspots. Through the time map analysis of keyword clustering, we found that the research hotspots gradually changed from "risk factors", "chronic periodontitis" and "psychosocial factors" to "inflammation", "Alzheimer's disease" and "smoking" and other keywords. Keyword analyses identify emerging research hotspots, including the interplay of stress, anxiety, and inflammation.

CONCLUSION: The number of related studies on periodontitis and depression continues to increase. The analysis of countries, authors and keywords reveals development trends, collaboration opportunities, and priority themes such as psychosocial factors and systemic inflammation. These findings provide a theoretical foundation for future research on periodontitis and depression.

RevDate: 2025-07-14

Totuk O, Çelem N, S Sahin (2025)

A young-onset dementia case associated with PDGFRβ mutation.

Journal of Alzheimer's disease reports, 9:25424823251359592.

We report a case of young-onset dementia (YOD) in a 40-year-old male with a heterozygous missense variant in the PDGFRβ gene. The patient exhibited progressive memory decline and disorientation. Brain MRI and cerebrospinal fluid biomarkers were consistent with Alzheimer's disease. Whole-exome sequencing identified a likely pathogenic PDGFRB c.1316G > A (p.Arg439Gln) variant. This report highlights a novel potential genetic contributor to vascular dysfunction and cognitive decline.

RevDate: 2025-07-14

Shan G, Y Zhang (2025)

Disease progression from mild cognitive impairment to dementia for patients with Alzheimer's disease or Lewy body pathology.

Journal of Alzheimer's disease reports, 9:25424823251359541.

BACKGROUND: The majority of mild cognitive impairment (MCI) patients who converted to dementia in later years have Alzheimer's disease (AD) pathology. The second most common type of dementia is Lewy body (LB) dementia.

OBJECTIVE: In this project, we are interested in identifying the risk factors that predict who will develop AD dementia or LB dementia in later years.

METHODS: Cox proportional hazards model and machine learning survival methods for interval-censored data were used to identify the risk factors that predict the onset of dementia for MCI patients with AD or LB pathology.

RESULTS: We found that orientation, memory, and irritability scores were useful in predicting AD dementia onset, while daily living, depression, and executive function scores were identified as strong predictors in the LB cohort.

CONCLUSIONS: Different neurocognitive domains were predictive for conversion to dementia from MCI in patients with AD or LB pathology. The depression scale and functional activities were found to be predictive of LB dementia while irritability or lability severity score from Neuropsychiatric Inventory Questionnaire was associated with the onset of AD dementia.

RevDate: 2025-07-14

Kodama N, Takahashi S, Tsuji M, et al (2025)

Possibility of screening for mild cognitive impairment via an eye tracking-based cognitive scale.

Frontiers in aging, 6:1532550.

INTRODUCTION: The Montreal Cognitive Assessment (MoCA) is widely used as a screening test for mild cognitive impairment (MCI). However, the MoCA takes approximately 15 min to administer and evaluate by skilled examiners, such as medical professionals. This study assessed whether an eye tracking-based cognitive scale using virtual reality (VR) was accurate and efficient to screen for MCI.

METHODS: This study included 143 patients. The Virtual Reality-Based Cognitive Function Examination (VR-E) was used with all participants to evaluate their memory, judgment, spatial cognition, calculation, and language function.

RESULTS: Significant differences were observed in all cognitive domains of memory, judgment, spatial cognition, calculation, and language function between the Alzheimer's disease (AD), MCI, and older healthy control (HC) groups. The area under the curve value of the VR-E score for the HC and MCI groups was 0.857, and that for the AD and MCI groups was 0.870. The correlation coefficient between the MMSE and VR-E scores was 0.566 (p < 0.001), and that between the Japanese version of the MoCA (MoCA-J) and VR-E scores was 0.648 (p < 0.001), which indicated a moderate correlation in both comparisons.

CONCLUSION: The VR-E had the same diagnostic performance results as the MoCA-J, thus the VR-E has potential for use in screening patients for MCI.

RevDate: 2025-07-14

Le TTM, Pham HT, Trinh HTT, et al (2025)

Huperzia javanica as a Novel Source of Huperzine Alkaloids and Huperzine-producing Fungi.

Indian journal of microbiology, 65(2):1201-1208.

Huperzine A (HupA) and huperzine B (HupB) are potent acetylcholinesterase inhibitor used widely for clinical treatment of Alzheimer's disease, which are mainly extracrted from natural populations of Huperzia species. This study aimed to the evaluate potential of producing Hup of native Huperzia javanica species collected in Vietnam as well as identify endophytic fungi that produce high Hup or simultaneously produce many types of Hup derived from this plant as a material source for natural Hup production. By HPLC-DAD-MS analysis, H. javanica collected from Ha Giang, Vietnam was found as a novel producer of HupA and HupB with a yield of 0.513 mg/g dry weight (wt) and 0.192 mg/g dry wt, respectively. Inspired by this discovery, a total of 63 endophytic fungi were isolated from healthy tissues of the collected H. javanica plants, including 52 fungal strains belonging to nine genera and 11 unidentified strains based on morphological characteristics. Using HPLC, 9 Hup-producing fungi were identified when compared to the standard HupA and HupB. Surprisingly, 7 fungal strains produced both HupA and HupB, among which strain TLC12 produced the highest HupA and HupB contents of 0.271 and 0.163 mg/g mycelium dry cell weight (gdcw), respectively. Fungal strains TLC19 and TLC22 only yielded a respective amount of 0.305 and 0.135 mg/ gdcw of HupA. Combining with Internal Transcribed Spacer sequence analysis, 9 potent fungi were identified as Neurospora calospora (TLC9, TLC10, TLC11), Schizophyllum commune TLC12, Epicoccum sorghinum TLC13, Alternaria tenuissima TLC14, Cephalotrichum sp. TLC20, Daldinia sp. TLC19, and Schizophyllum sp. TLC22. To the best of our knowledge, this is the first report demonstrating H. javanica as a prolific and novel source of endophytic fungi capable of yielding high HupA and HupB contents. The exploitation of 9 Hup-producing fungi is also valuable for both basic research and industrial Hup manufactures. These findings open new perspectives for industrial production of fungal HupA and HupB and conservation of Huperzia species.

RevDate: 2025-07-14

Maraghi E, Safarpour AR, Hajmohammadi M, et al (2025)

Effect of Anticholinergic Medications on the Risk of Dementia: A Systematic Review and Meta-analysis Protocol.

Basic and clinical neuroscience, 16(1):55-64.

INTRODUCTION: The most frequent dementia is senile dementia or Alzheimer disease. Meanwhile, anticholinergic drugs can potentially modify the risk factors. As different studies have achieved dissimilar results and the clinical findings of these interventions have not been conclusive, the objective of this research will be to evaluate the effect of anticholinergic drugs on the risk of dementia.

METHODS: This systematic review and meta-analysis with no language limitation will search WoS, EMBASE, and MEDLINE via PubMed, Scopus, ProQuest electronic databases, and Grey Literature between December 15, 1988, and December 15, 2021. Our search strategy with suitability criteria covers cohort, case-control, nested case-control, randomized, and non-randomized clinical trial studies evaluating the effect of anticholinergic drugs on the risk of dementia. Two authors will independently implement the selection phase, data extraction, and quality assessment. The reviewers will evaluate the risk of bias using the Newcastle-Ottawa, Cochrane risk of bias tool and ROBINS-I (risk of bias in non-randomized studies - of interventions) quality assessment scale. We will conduct a meta-analysis with a random or fixed effect model according to the severity of methodological heterogeneity. The results will be presented via the forest plot for the final studies' data composition, demonstrating the separated and combined frequency and their corresponding 95% CIs, summary tables, and narrative summaries.

CONCLUSION: The results of different studies in this field are various. This study's findings and other studies will help physicians and other health professionals before prescribing these drugs. Older people, especially those with polypharmacy, should be carefully assessed for the risk of dementia, Alzheimer or a variety of cognitive disorders.

RevDate: 2025-07-14

Ouyang J, Zhao Q, Adeli E, et al (2024)

SOM2LM: Self-Organized Multi-Modal Longitudinal Maps.

Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention, 15002:400-410.

Neuroimage modalities acquired by longitudinal studies often provide complementary information regarding disease progression. For example, amyloid PET visualizes the build-up of amyloid plaques that appear in earlier stages of Alzheimer's disease (AD), while structural MRIs depict brain atrophy appearing in the later stages of the disease. To accurately model multi-modal longitudinal data, we propose an interpretable self-supervised model called Self-Organized Multi-Modal Longitudinal Maps (SOM2LM). SOM2LM encodes each modality as a 2D self-organizing map (SOM) so that one dimension of each modality-specific SOMs corresponds to disease abnormality. The model also regularizes across modalities to depict their temporal order of capturing abnormality. When applied to longitudinal T1w MRIs and amyloid PET of the Alzheimer's Disease Neuroimaging Initiative (ADNI, N=741), SOM2LM generates interpretable latent spaces that characterize disease abnormality. When compared to state-of-art models, it achieves higher accuracy for the downstream tasks of cross-modality prediction of amyloid status from T1w-MRI and joint-modality prediction of individuals with mild cognitive impairment converting to AD using both MRI and amyloid PET. The code is available at https://github.com/ouyangjiahong/longitudinal-som-multi-modality.

RevDate: 2025-07-14

Midthune B, Park G, Tyan SH, et al (2025)

Caspase cleavage of APP contributes to amyloid beta-protein induced synaptic injury.

bioRxiv : the preprint server for biology pii:2025.04.30.651606.

BACKGROUND: Increasing evidence suggests that amyloid beta (Aβ) lies at the center of Alzheimer's Disease (AD) pathology and that synapses are the initial site of damage by Aβ. Recent studies have also indicated a role for caspases in AD-related synaptic dysfunction and memory loss, but the mechanism(s) through which the caspases act remains elusive. Previous studies in cell culture indicate that cleavage of a caspase site on the intracellular domain of the amyloid precursor protein (APP) protein contributes to Aβ-induced cell death. However, the role of this cleavage event in synaptic dysfunction has not been established.

METHODS: Through a combination of intracellular and extracellular electrophysiological methods and confocal microscopy of dendritic spines, we examined the involvement of caspase-3 and amyloid-precursor protein in Aβ-mediated synaptic dysfunction.

RESULTS: Here, we provide evidence that caspase activity at the intracellular domain of APP is required for acute Aβ-induced depression of glutamatergic synapses. We find that local elevation of Aβ levels through over-expression of the C-terminal fragment of APP (C99) failed to depress synapses if caspases were inhibited pharmacologically or in tissue lacking caspase-3. To demonstrate a link between these findings to APP, we found that Aβ failed to depress synaptic transmission or inhibit synaptic plasticity in neurons lacking APP. To specifically test the role of caspase cleavage of the intracellular domain of APP, we introduced a mutation that inhibits caspase cleavage at site 664 to the C99 construct; this construct produced Aβ but failed to elicit Aβ-induced synaptic depression or spine loss, and reduced caspase-3 activity.

CONCLUSION: Taken together, these results suggest an APP-dependent pathway in which caspases contribute to Aβ-induced synaptic depression and spine loss via cleavage of APP.

RevDate: 2025-07-14

Watanabe R, Creekmore BC, Darwich NF, et al (2025)

Repositioning of polyubiquitin alters the pathologic tau filament structure.

bioRxiv : the preprint server for biology pii:2025.05.02.651930.

Structurally diverse tau filaments form proteinaceous aggregates in a heterogeneous group of neurodegenerative diseases called tauopathies [1] . The factors extrinsic to the highly ordered core structure that influence tau filament stability are not well understood. Here, we found that polyubiquitinated tau filaments from Alzheimer's disease and vacuolar tauopathy human brain tissue exhibit distinct seeding patterns in mice, in association with differences in tau filament ultrastructure determined by cryo-electron microscopy. Interestingly, chemical modulation of the polarity of polyubiquitin adjacent to the tau core with the small molecule ubistatin B resulted in the repositioning of poorly structured densities towards positively charged residues on the highly structured core filament, leading to shifting of the protofilament-protofilament interface of certain vacuolar tauopathy tau filaments. These results suggest that the structure of tau filaments that are associated with different seeding activities in vivo can be influenced by post-translational modifications.

RevDate: 2025-07-14

Song Z, Huang X, Jannu AJ, et al (2025)

Identify Alzheimer's disease subtypes and markers from multi-omic data of human brain and blood with a subspace merging algorithm.

bioRxiv : the preprint server for biology pii:2025.04.30.651565.

Identifying Alzheimer's disease (AD) subtypes is essential for AD diagnosis and treatment. We integrated multiomics data from brain tissues of the ROSMAP and MSBB studies using a subspace merging algorithm and identified two AD patient clusters with notable cognitive and AD pathology differences. Analysis of differentially expressed genes (DEGs) in brain and blood samples pinpointed the LDLR gene as a potential blood biomarker linked to brain gene expression changes. Furthermore, we conducted PheWAS analysis on All of Us Project's EHR and WGS dataset for 105 eQTLs associated with the DEGs and revealed significant associations between these eQTLs and several phenotypes, shedding light on potential regulatory roles of these genes in diverse physiological processes. Our study successfully integrated multiomics data and proposes LDLR as a candidate blood biomarker for AD subtyping. The identified phenotypic signatures provide valuable insights on molecular mechanisms underlying AD heterogeneity, paving the way for personalized AD treatment.

RevDate: 2025-07-14

Gaspar L, Bartman S, Tobias-Wallingford H, et al (2025)

Short-Term Exposure to Polystyrene Microplastics Alters Cognition, Immune, and Metabolic Markers in an APOE Genotype and Sex-Dependent Manner.

bioRxiv : the preprint server for biology pii:2025.05.02.651942.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders and one of the leading causes of death in individuals over the age of 65. Most cases of AD develop sporadically, however, there are several risk factors that have been identified which significantly increases an individual's risk for developing AD. The most prominent of these is Apolipoprotein E4 (APOE4), which can potentially result in an up to 10-fold greater risk of developing AD. The presence of APOE4 alone, however, cannot be solely responsible for AD as the disease may occur even in the absence of APOE4. Therefore, there must be other contributing factors such as exposure to environmental toxins including heavy metals and pesticides, which have independently been shown to contribute to AD. Nano- and microplastics (NMPs) are plastic particles less than 1 μm and 5 mm in size, respectively, and have only recently been identified as a major environmental pollutant with serious health concerns. Given the adverse health effects that are increasingly being associated with NMPs exposure, we sought to understand how the combination of APOE4 and NMPs exposure may work synergistically to promote cognitive dysfunction and alter key regulatory pathways to impact overall health. Following an acute (3 week) exposure to pristine spherical fluorescently-labeled 0.1 and 2 µm polystyrene (PS) NMPs, we found significant sex-dependent alterations in locomotor and recognition memory in APOE4 mice, but not in APOE3 controls. We additionally found that exposure to PS-NMPs resulted in sex and genotype specific alterations in astrocytic and microglial markers in the brain, and in CYP1A1, a major metabolizer of environmental polycyclic aromatic hydrocarbons, in the liver. These results suggest PS-NMPs may interact with the APOE4 allele to promote cognitive dysfunction and alter immune and metabolic pathways which may contribute to disease-like states.

RevDate: 2025-07-14

Hawkinson TR, Liu Z, Ribas RA, et al (2025)

Hyper-Glycosylation as a Central Metabolic Driver of Alzheimer's Disease.

bioRxiv : the preprint server for biology pii:2025.04.30.651461.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by devastating degenerative decline. Metabolic disruptions are widely observed, yet their involvement in the molecular etiology of AD remains underexplored. Utilizing spatial metabolomics, lipidomics, and glycomics in both mouse models and human post-mortem samples, we identified a hyper-glycosylation phenotype as a hallmark of AD. To investigate the underlying mechanisms and whether the observed effect was a driver of the observed decline, we developed an advanced spatial isotopic tracing pulse-chase method to study the dynamics of N-linked glycans. Our analysis revealed enhanced glycan biosynthesis in AD mouse models. Based on these findings, we performed genetic and dietary interventions to modulate glycan biosynthesis. Genetic knockdown of glycan biosynthetic enzymes ameliorated the hyper-glycosylation and improved cognitive and behavioral outcomes in AD mice. In contrast, oral glucosamine supplementation drove hyper-glycosylation and exacerbated cognitive and behavioral deficits. To assess the clinical relevance of these findings, we conducted a retrospective analysis of a large population of patients with mild cognitive impairment (MCI), AD, and Alzheimer's Disease Related Dementias (ADRD) stratified by glucosamine use, leveraging electronic health records. Consistently, glucosamine supplementation was associated with increased mortality in AD and ADRD patient cohorts, and significantly elevated progression from MCI to AD compared to age-matched controls. Collectively, our findings establish hyper-glycosylation as a pathological driver of AD and highlight glycan metabolism as an actional target in the fight against AD.

RevDate: 2025-07-14

Victor MB, Sun N, Galani K, et al (2025)

Cellular and Regional Vulnerability Shapes the Molecular Landscape of Psychosis in Alzheimer's Disease.

bioRxiv : the preprint server for biology pii:2025.04.30.651435.

UNLABELLED: Approximately 40% of Alzheimer's disease (AD) patients develop psychosis, yet the molecular and cellular processes that govern the manifestation of psychotic symptoms in dementia remain poorly understood. To define the neurobiological correlates that distinguish AD patients with psychosis (AD+P) from AD patients that never exhibited psychotic symptoms (AD-P), we performed single-nucleus transcriptome and epigenome profiling from prefrontal cortex and hippocampus of 48 postmortem brains from AD subjects segmented by psychiatric diagnosis. Our snRNA-seq profiling uncovered differentially expressed genes (DEGs) across multiple cell types, including transcriptional signatures of enhanced synaptic transmission in upper-layer pyramidal neurons of the AD+P cortex. Cell fraction analysis and histology both indicate greater loss of upper-layer pyramidal neurons in AD+P in comparison to AD-P cortex. Integrating our snRNA-seq data with functional screens in stem-cell derived brain organoids, we defined how genetic perturbations modify input-output network connectivity in vitro in a model of cortico-cortical communication. We find that differential vulnerability of pyramidal neurons in AD+P is associated with CDK5/p35-associated neurotoxicity and IL6-mediated glial inflammatory expression changes. This neuronal response is associated with microglial exhaustion and astrocytic inflammation signatures triggered by layer-specific neuropathological changes in the brains of AD+P patients. Lastly, we elucidate common and distinct transcriptional signatures between psychosis in AD and several other psychiatric conditions, and found significant enrichment of schizophrenia genetics with AD+P that is most convergent in upper-layer pyramidal neurons. Our work provides novel insight into the pathophysiological role of hyperexcitable circuits in the etiology of neuropsychiatric symptoms of AD.

HIGHLIGHTS: Cell-type- and brain-region-specific transcriptional changes in AD with psychosis (AD+P)Upper-layer pyramidal dysfunction and metabolic vulnerability marks the pathophysiology of AD+PCircuit wiring programs are evoked in AD+P as maladaptive compensatory responsesAD+P-associated IL-6 signaling impairs neuronal network function in brain organoids.

RevDate: 2025-07-14

Mekkittikul M, Zhu C, Danna BT, et al (2025)

[13] C tracing in synaptosomes reveals that SGLT2 inhibition with dapagliflozin prevents metabolic deficits in the 5X-FAD model of Alzheimer's Disease.

bioRxiv : the preprint server for biology pii:2025.04.30.651373.

Metabolic dysfunction is linked to several forms of age-related neurodegeneration including Alzheimer's Disease (AD), and targeting brain energy metabolism is an increasingly attractive mode of therapeutic intervention. However, commonly used in vitro methods to identify specific metabolic pathways of interest in preclinical models of neurodegenerative disease have considerable limitations. They are prone to subselection of sample material, unable to identify cell type-specific effects, or cannot identify metabolic defects upstream of mitochondria. Here we address these challenges by validating a method for stable isotope tracing with isolated synaptic nerve terminals, or 'synaptosomes'. We further applied this approach to study glucose metabolism in synaptosomes isolated from the 5X-FAD mouse model of AD treated with the antidiabetic sodium-glucose linked transporter-2 (SGLT-2) inhibitor Dapagliflozin. Treatment with Dapagliflozin preserved steady-state levels of synaptosomal metabolites and enrichment from labeled glucose into citrate that was reduced in the 5X-FAD model. These changes correlated with trends towards improved spatial working memory but not amyloid burden. The results highlight the utility of stable isotope tracing in synaptosomes to identify precise sites of metabolic dysfunction and mechanisms of action for metabolic drug candidates in preclinical models of neurodegeneration.

RevDate: 2025-07-14

Van Zuiden W, Meimoun TD, Bar C, et al (2025)

TDP-43 toxic gain of function links ALS, FTD and Alzheimer's Disease through splicing dysregulation.

bioRxiv : the preprint server for biology pii:2025.04.20.648873.

Loss of nuclear TDP-43 splicing activity is a common feature across neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but its relevance to Alzheimer's disease (AD) remains unclear. Here, we show that TDP-43 pathology in AD is broadly associated with splicing abnormalities, including aberrant splicing of amyloid precursor protein (APP). TDP-43 drives the formation of elongated APP isoforms, disrupting alternative splicing across ALS, FTLD-TDP and AD, providing a compelling mechanism for a long-standing observation of APP isoform dysregulation. We further establish a mechanistic link between TDP-43, APP splicing, and A-beta pathology. Surprisingly, the disruption to alternative APP splicing is mediated by a toxic gain of cytoplasmic TDP-43 function, rather than loss of its nuclear role. Using proximity proteomics and base editing in human iPSC-derived neurons, we show that TDP-43 pathology causes cytoplasmic co-sequestration of splicing regulators SCAF11, SRSF5, and TIAL1. Knockdown of these regulators also results in APP mis-splicing and increased A-beta burden, without affecting other TDP-43 targets such as STMN2 or UNC13A. Together, our findings suggest that TDP-43-mediated splicing dysfunction upstream of APP contributes to the pathogenesis of seemingly disparate neurodegenerative diseases, uniting AD and ALS/FTLD-TDP through a shared molecular mechanism.

RevDate: 2025-07-14

Meade J, Mesa H, Liu L, et al (2025)

Synaptic Toxicity of OGA Inhibitors and the Failure of Ceperognastat.

bioRxiv : the preprint server for biology pii:2025.05.09.648606.

O-GlcNAcase inhibitors (OGAi) have been proposed as therapeutics for Alzheimer's disease due to their ability to increase O-GlcNAcylation of tau and reduce its aggregation. However, the recent failure of ceperognastat in a Phase II trial-marked by accelerated cognitive decline in the treatment arm-has raised concerns about the safety of this therapeutic class. Here, we evaluated the acute synaptic effects of three structurally distinct OGAi (ceperognastat, ASN90, and MK8719) in mouse hippocampal slices. Electrophysiological recordings revealed that all three compounds impaired both short- and long-term synaptic plasticity, as evidenced by reduced paired-pulse facilitation/depression and suppressed long-term potentiation. Immunohistochemistry showed altered synaptic protein levels, with increased PSD-95 and reduced Synaptophysin 1 in neurons, alongside a biphasic shift in Tau phosphorylation. These findings indicate that OGAi produce rapid and convergent synaptotoxic effects across pre- and postsynaptic compartments, likely reflecting a class-wide mechanism. We argue that electrophysiological screening should be standard in CNS drug development and caution against targeting essential synaptic processes in chronic neurodegenerative conditions.

RevDate: 2025-07-14

Libera JL, Hu J, Nguyen TA, et al (2025)

Loss of age-associated increase in m [6] A-modified RNA contributes to GABAergic dysregulation in Alzheimer's disease.

bioRxiv : the preprint server for biology pii:2025.05.02.651974.

UNLABELLED: Dysregulated RNA metabolism is a significant feature of Alzheimer's disease (AD), yet how post-transcriptional RNA modifications like N [6] -methyladenosine (m [6] A) are altered in AD is unknown. Here, we performed d eamination a djacent to R NA modification targets (DART-seq) on human dorsolateral prefrontal cortices to assess changes in m [6] A with nucleotide resolution. In non-AD brains, m [6] A sites increased with age, predominantly within the 3'UTR of transcripts encoding tripartite synapse proteins. In contrast, AD brains lost the age-associated m [6] A site increase and exhibited global hypomethylation of transcripts, including MAPT and APP . Hypomethylated genes involved with GABAergic signaling, glutamate transport, and ubiquitin-mediated proteolysis exhibited reduced expression, connecting m [6] A to synaptic excitotoxicity and disrupted proteostasis in AD. Site-specific m [6] A levels were linked with GABRA1 expression and protein levels, but this relationship was abolished in AD. Our findings provide insight into post-transcriptional mechanisms of dysregulated RNA metabolism in AD that are related to aging and GABAergic regulation.

HIGHLIGHTS: With age, the number of m [6] A sites increases among Control cases (lacking AD pathology) but remains unchanged in AD cases. Transcripts are globally hypomethylated in AD cases.Hypomethylation is linked to decreased mRNA expression of transcripts related to synaptic and proteostatic function in AD. 3'UTR-localized m [6] A sites lack typical association with transcript metabolism of GABRA1 in AD.

RevDate: 2025-07-14

Pantula A, Zhou B, Morales Pantoja IE, et al (2025)

Computational modeling of necrosis in neural organoids.

bioRxiv : the preprint server for biology pii:2025.04.30.651571.

Neural organoids (NOs), also known as brain organoids, are derived from human-induced pluripotent stem cells and are Microphysiological Systems (MPS) of the brain that can recapitulate key aspects of neurodevelopment. They enable in vitro studies of brain development and disease mechanisms, providing disease models for various neurodegenerative or neurodevelopmental/degenerative disorders like Alzheimer's disease, microcephaly, and autism. There are many protocols to generate NOs with different complexities and sizes, varying from 400 μm to several mm in diameter, with a starvation-induced necrotic core eventually forming depending on the diameter and culture conditions. Thus, they can benefit from vascularization and more optimal culture conditions. There have been several attempts to decrease necrosis while growing larger NOs, such as by using orbital shaking or 2D/3D microfluidic chips, but only with limited success. In this study, we describe a 3D finite element model to simulate O 2 starvation-induced necrosis in NOs using the Damköhler Number (Da) and the Michaelis-Menten kinetics. We measured the necrotic areas in NOs using fluorescent imaging and used them to calibrate the model with a specific Da . Using these calibrated values, we systematically compared simulations of different NO culture methods-static, orbital shaking, and microfluidic flow around organoids-highlighting their relative impacts on nutrient diffusion and necrosis. We observed that these culture strategies cannot prevent necrosis beyond a diameter of ∼800 μm. Based on these findings, we propose that 3D spatial perfusion, achieved through uniformly distributed fluidic capillaries within the NO, could significantly reduce necrosis. We conducted parametric studies on capillary spacing, density, and layout. Our calibrated model offers insights for designing next-generation microfabricated bioreactors and culture devices, not just for NOs but also for all 3D tissue engineering and organoid research.

RevDate: 2025-07-14

Fremuth LE, van de Vlekkert D, Hu H, et al (2025)

Targeting Lysosomal Dysfunction to Alleviate Plaque Deposition in an Alzheimer Disease Model.

bioRxiv : the preprint server for biology pii:2025.04.28.651121.

Alzheimer disease (AD) is characterized by aberrant amyloid precursor protein (APP) processing and lysosomal dysfunction. This study identifies two members of the lysosomal multi-enzyme complex (LMC), neuraminidase 1 (Neu1) and protective protein/cathepsin A (PPCA), as a critical regulators of APP metabolism. Neu1 deficiency in human AD brains and 5xFAD/ Neu1 [-/-] mice leads to sialic acid retention on APP and its secretases, enhancing amyloidogenic cleavage and Aβ42 production. Additionally, Neu1 deficiency increases lysosomal exocytosis, contributing to extracellular Aβ release and neuroinflammation. Conversely, overexpression of PPCA in neurons or co-expression of PPCA and NEU1 normalizes sialylation patterns, reduces secretase activity, and mitigates plaque burden. These findings reveal a novel bidirectional dependency between Neu1 and PPCA, underscoring their cooperative role in maintaining lysosomal homeostasis. Additionally, AAV-mediated co-expression of NEU1 and PPCA in 5XFAD brains demonstrates therapeutic potential by reducing amyloid pathology. These findings position lysosomal dysfunction and the Neu1-PPCA axis as promising targets for therapeutic intervention in AD.

RevDate: 2025-07-14

Asaba T, Hamano S, Nanmo A, et al (2025)

Human iPSC-derived cerebral organoids reveal oxytocin-mediated protection against amyloid-β pathology.

Regenerative therapy, 30:259-267.

INTRODUCTION: Neuroinflammation is a key contributor to the pathogenesis of Alzheimer's disease (AD), and impaired clearance of amyloid-β (Aβ) by microglia is closely associated with disease progression. Oxytocin (OXT), a hypothalamic neuropeptide, has recently been reported to exert anti-inflammatory effects on microglia; however, its therapeutic potential in the human brain remains unclear.

METHODS: We generated human cerebral organoids (hCOs) from induced pluripotent stem cells (iPSCs) to model early AD-like pathology. Aβ toxicity was induced by applying 3 μM Aβ1-42 for 48 h. The protective effects of OXT were evaluated through immunohistochemistry, RT-qPCR, calcium imaging, and multielectrode array (MEA) recordings. The involvement of microglia in Aβ clearance was assessed by immunostaining and gene expression analysis of TREM2.

RESULTS: Aβ exposure led to significant deposition of Aβ in the outer layers of hCOs, accompanied by suppressed neural activity and increased apoptotic signaling. Pretreatment with OXT attenuated Aβ deposition and caspase-3-mediated apoptosis in a concentration-dependent manner. OXT also restored calcium oscillations and neuronal network activity as measured by MEA. Notably, OXT enhanced the recruitment of microglia to Aβ deposits and upregulated the expression of TREM2, a key regulator of microglial phagocytosis. Co-expression of oxytocin receptors (OXTR) on Iba1-positive microglia suggests that OXT directly modulates microglial activation and Aβ clearance.

CONCLUSIONS: OXT has neuroprotective effects on human cortical organoids by preserving their neuronal activity and promoting microglial-mediated Aβ clearance. This study provides novel insights into the therapeutic potential of OXT for targeting neuroinflammation and Aβ pathology in patients with AD.

RevDate: 2025-07-14

Wang Z, Zhang K, Huang M, et al (2025)

Structures and functions of the MICOS: Pathogenesis and therapeutic implications in Alzheimer's disease.

Acta pharmaceutica Sinica. B, 15(6):2966-2984.

Mitochondrial dysfunction is a critical factor in the pathogenesis of Alzheimer's disease (AD). The mitochondrial contact site and cristae organizing system (MICOS) plays a pivotal role in shaping the inner mitochondrial membrane, forming cristae junctions and establishing interaction sites between the inner and outer mitochondrial membranes and thereby serving as a cornerstone of mitochondrial structure and function. In the past decade, MICOS abnormalities have been extensively linked to AD pathogenesis. In particular, dysregulated expression of MICOS subunits and mutations in MICOS-related genes have been identified in AD, often in association with hallmark pathological features such as amyloid-β plaque accumulation, neurofibrillary tangle formation, and neuronal apoptosis. Furthermore, MICOS subunits interact with several etiologically relevant proteins, significantly influencing AD progression. The intricate crosstalk between these proteins and MICOS subunits underscores the relevance of MICOS dysfunction in AD. Therapeutic strategies targeting MICOS subunits or their interacting proteins may offer novel approaches for AD treatment. In the present review, we introduce current understanding of MICOS structures and functions, highlight MICOS pathogenesis in AD, and summarize the available MICOS-targeting drugs potentially useful for AD.

RevDate: 2025-07-14

Xu Y, Ye X, Du Y, et al (2025)

Nose-to-brain delivery of targeted lipid nanoparticles as two-pronged β-amyloid nanoscavenger for Alzheimer's disease therapy.

Acta pharmaceutica Sinica. B, 15(6):2884-2899.

Alzheimer's disease (AD), characterized by β-amyloid (Aβ) aggregation and neuroinflammation, remains a formidable clinical challenge. Herein, we present an innovative nose-to-brain delivery platform utilizing lactoferrin (Lf)-functionalized lipid nanoparticles (LNPs) co-encapsulating α-mangostin (α-M) and β-site APP cleaving enzyme 1 (BACE1) siRNA (siB). This dual-modal therapeutic system synergistically combines the neuroprotective and microglia-reprogramming capabilities of α-M with the transcriptional silencing of BACE1 via siB, thereby simultaneously inhibiting Aβ production and enhancing its clearance. Fabricated via a microfluidic approach, the LNPs exhibited uniform particle size distribution, great encapsulation efficiency, and robust colloidal stability. Upon intranasal administration, Lf-functionalization enabled superior brain-targeting efficacy through receptor-mediated transcytosis. In vitro studies demonstrated that α-M reversed Aβ-induced low-density lipoprotein receptor downregulation, promoting microglial phagocytosis and autophagic degradation of Aβ, while siB effectively suppressed BACE1 expression, abrogating Aβ synthesis. In vivo investigations in APP/PS1 transgenic mice revealed remarkable cognitive recovery, substantial Aβ plaque reduction, and alleviation of neuroinflammation and oxidative stress. This intricately designed LNP system, exploiting a non-invasive and efficient nose-to-brain delivery route, provides a biocompatible, synergistic, and transformative therapeutic strategy for the multifaceted management of AD.

RevDate: 2025-07-14

Ren L, Ma X, J Ye (2025)

Mechanism of Alzheimer's disease treatment by sound and light stimulation.

Acta pharmaceutica Sinica. B, 15(6):3346-3348.

RevDate: 2025-07-14

Madamanchi K, Zhang J, GC Melkani (2025)

Linkage of circadian rhythm disruptions with Alzheimer's disease and therapeutic interventions.

Acta pharmaceutica Sinica. B, 15(6):2945-2965.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and pathological brain changes. While aging is the primary risk factor, circadian rhythm disruption (CRD) is increasingly recognized as a central driver of AD pathology. CRD exacerbates oxidative stress, systemic inflammation, and gut microbiome dysbiosis, impairing sleep-wake cycles, disrupting metabolic homeostasis, and promoting neuroinflammation, ultimately accelerating disease progression. Oxidative stress, a key factor in neuronal damage, is both a cause and consequence of circadian misalignment, while mitochondrial dysfunction further amplifies oxidative damage, impairing synaptic function and cognitive stability. Additionally, gut microbiome dysbiosis contributes to neuroinflammatory processes, worsening neurodegeneration. Given these complex interactions, this review aims to elucidate the role of CRD in AD pathology and explore potential therapeutic interventions targeting circadian dysfunction. Specifically, it examines the efficacy of time-restricted feeding (TRF), a dietary strategy that aligns food intake with circadian rhythms. TRF has shown promise in restoring circadian function, reducing oxidative stress, improving mitochondrial health, and promoting gut microbiome diversity. By addressing CRD, TRF may offer a novel approach to mitigating AD pathologies. This review also identifies current research gaps and future directions for developing circadian-based interventions in AD prevention and treatment.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Cho J, Birchfield T, Thorud JL, et al (2025)

GamePlan4Care, a Web-Based Adaptation of the Resources for Enhancing Alzheimer's Caregiver Health II Intervention for Family Caregivers of Persons Living With Dementia: Formative, Qualitative Usability Testing Study.

JMIR formative research, 9:e60143 pii:v9i1e60143.

BACKGROUND: The negative consequences of caregiving can be mitigated by providing caregivers with support programs that increase their dementia care skills and provide emotional and tangible support. Web-based technology can increase the availability of evidence-based caregiver interventions. GamePlan4Care (GP4C) is a web-based adaptation of the Resources for Enhancing Alzheimer's Caregiver Health II (REACH II) intervention, redesigned and reformatted for web-based delivery.

OBJECTIVE: The goal of GP4C is to create a web-based family caregiver support platform that facilitates self-directed exposure to evidence-based skills training and support for caregivers of persons living with dementia. This multidimensional approach of using technology enhanced with live support has the potential for improved scalability and sustainability. In preparation for a randomized clinical trial of the new intervention, the GP4C platform underwent user interface/user experience (UI/UX) testing with caregivers as part of an iterative design process.

METHODS: UI/UX testing of caregivers' reactions to technical and content-related aspects of the platform was conducted with 31 caregivers recruited through partnerships with community-based organizations in central Texas. Usability testing consisted of performing system tasks, answering open-ended questions on the tasks, and providing feedback on their experience with the platform. Two researchers used an inductive thematic approach to data analysis using transcripts of individual audio and screen-recorded sessions with each participant. The analysis consisted of 3 phases: data familiarization, coding, and theme formulation.

RESULTS: In total, 18 participants tested technical-related aspects of the GP4C platform, and 13 participants tested content-related aspects. The average age of participants was 62 (SD 12.2, range 31-86). A majority of participants were female (27/31, 87.1%) and White or Caucasian (26/31, 83.1%) while almost one-third were Hispanic (10/31, 32.3%). The thematic analysis revealed 3 themes: supportive resources as a common theme, active engagement for technical aspects of the platform, and a comprehensive approach for content aspects of the platform. Participants also suggested changes in navigation and content.

CONCLUSIONS: Findings from the usability testing sessions indicate that the platform provided engaging, useful content that the caregiver would continue to use, resonated with their caregiving experience, helped the caregivers think through their choices and emotions, and could be used to help communicate with the person living with dementia. Caregivers appreciated the personalization based on what they had already completed and the concept of having a Dementia Care Navigator when they needed additional help. Caregivers also provided multiple suggestions on how to improve the system, including changes for easier navigation and inclusiveness. This positive feedback indicates that with a few changes, the platform would be beneficial to meet the needs and provide resources for caregivers of persons living with dementia. The process of involving end users in usability testing during the development stage ensures that the finished tool will better meet users' expectations and current needs.

RevDate: 2025-07-14

Lou Y, Du M, Wang P, et al (2025)

Semiparametric regression analysis of interval-censored failure time data with a cure subgroup and nonignorable missing covariates.

Statistical methods in medical research [Epub ahead of print].

This article discusses regression analysis of interval-censored failure time data in the presence of a cure fraction and nonignorable missing covariates. To address the challenges caused by interval censoring, missing covariates and the existence of a cure subgroup, we propose a joint semiparametric modeling framework that simultaneously models the failure time of interest and the missing covariates. In particular, we present a class of semiparametric nonmixture cure models for the failure time and a semiparametric density ratio model for the missing covariates. A two-step likelihood-based estimation procedure is developed and the large sample properties of the resulting estimators are established. An extensive numerical study demonstrates the good performance of the proposed method in practical settings and the proposed approach is applied to an Alzheimer's disease study that motivated this study.

RevDate: 2025-07-14

Okada Y, Ohno N, Kitahara Y, et al (2025)

Voxel-Based Specific Regional Analysis System for Alzheimer's Disease and Arterial Spin Labeling in Brain Magnetic Resonance Imaging: A Comparative Study.

Current medical imaging pii:CMIR-EPUB-149308 [Epub ahead of print].

Introduction: Magnetic resonance imaging can differentiate Alzheimer-type dementia from dementia with Lewy bodies using voxel-based specific regional analysis systems for Alzheimer's disease and arterial spin labeling, which reveal reduced blood flow from the posterior cingulate gyrus to the precuneus in Alzheimer-type dementia. However, the relationship between voxel-based specific regional analysis system scores and arterial spin labeling remains unclear. To investigate the relationship between brain atrophy scores and arterial spin labeling values in the posterior cingulate precuneus.

Methods: Participants with suspected dementia who underwent brain magnetic resonance imaging using a voxel-based regional analysis system were included. They were classified as follows: Group 1 (suspected Alzheimer-type dementia) had atrophy ≥2 in the volume of interest; Group 2 (suspected dementia with Lewy body) had atrophy <2 in the volume of interest and ≥0.2 in the gray and white matter of the dorsal brainstem; and Group 3 included those not meeting these criteria. Correlation values among atrophy within the volume of interest, percentage of atrophic areas, atrophy ratio, percentage of total brain atrophy, age, and maximum arterial spin labeling value at the posterior cingulate precuneus were evaluated.

Results: Groups 1, 2, and 3 comprised 179, 143, and 197 patients, respectively. Arterial spin labeling values at the posterior cingulate precuneus were 77.0±24.4-77.3±25.2, 78.3±81.3-80.2±23.6, and 80.2±22.3-80.4±22.8 mL/min/100 g, respectively. Group 1 had a correlation coefficient between total brain atrophy and arterial spin labeling of -0.189 to-0.214 (P<0.01). Group 2 had a correlation coefficient between total brain atrophy and arterial spin labeling of -0.215 to -0.223 (P<0.01). Group 3 showed no significant correlations. No statistically significant difference was observed in ASL 1 and 2 values between the Alzheimer-type dementia and other groups (ASL 1: 74.5 mL/min/100 g vs. 78.8 mL/min/100 g, P=0.08; ASL 2: 74.8 mL/min/100 g vs. 79.2 mL/min/100 g, P=0.101). No statistically significant difference was observed in ASL 1 and 2 values between the Alzheimer-type dementia and DLB groups (ASL 1: 74.5 mL/min/100 g vs. 69.3. mL/min/100 g, P=0.093; ASL 2: 74.8 mL/min/100 g vs. 78.9 mL/min/100 g, P=0.258).

Discussion: Reduced blood flow in the posterior cingulate gyrus and precuneus shows only a weak correlation with brain atrophy in both Alzheimer-type dementia and dementia with Lewy bodies. Therefore, it is not a reliable marker for differentiating Alzheimer-type dementia from dementia with Lewy bodies and other groups.

Conclusion: It is necessary to avoid using cerebral blood flow assessment alone when diagnosing dementia.

.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Sudzik D, Bal W, NE Wezynfeld (2025)

Oxidative Activity of Copper Ions in Ternary Systems With N-Truncated Amyloid Beta Peptides and Low Molecular Weight Substances.

Journal of neurochemistry, 169(7):e70145.

Oxidative stress is one of the most characteristic features of Alzheimer's disease. Previous studies revealed that copper complexes of amyloid beta (Aβ) peptides, mainly the Aβ1-x form, could effectively catalyze the production of reactive oxygen species (ROS), causing the oxidation of physiological compounds. The Cu(II) binding to N-truncated Aβ forms containing His-2 and His-3 motifs produced less oxidative damage by arresting the Cu(II) ions in highly stable Cu(II)/Aβ complexes. This could be reversed, however, by interactions with low molecular weight (LMW) substances. In this work, we investigated the influence of biologically relevant LMW: His-1 dipeptide His-Leu, histidine, imidazole, and neurotransmitters histamine, glycine, and glutamate on the ROS-related ascorbate oxidation by Cu(II) complexes of Aβ peptides comprising the His-2 and His-3 motifs, namely Aβ4-9, Aβ5-9, and Aβ12-16. These peptides are putative products of Aβ hydrolysis by protease neprilysin. A significantly higher efficiency in the ascorbate oxidation was observed for the ternary Cu(II)/Aβ/LMW systems with His-Leu and histidine compared to the binary Cu(II)/Aβ complexes. The effect was more pronounced for the systems with Aβ4-9 (the His-3 motif only) than those with Aβ5-9 and Aβ12-16 (containing the His-2 motif), which is likely connected with a faster Cu(II) trapping by the His-2 peptides compared to the His-3 peptides. The obtained results raise further questions regarding the copper redox activity in Alzheimer's disease.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Bezerra IC, Dos Santos ERS, do Nascimento KGA, et al (2025)

Label-Free Proteomic Profiling of the dvls2 (CL2006) Caenorhabditis elegans Alzheimer's Disease (AD) Model Reveals Conserved Molecular Signatures Shared With the Human AD Brain.

Journal of neurochemistry, 169(7):e70152.

Alzheimer's disease (AD) is the most common form of dementia, posing significant challenges to cognitive, emotional, social, and financial well-being. The biochemical and molecular pathways associated with AD are complex, making it difficult to study and simulate in patients or through in vitro research. Thus, animal models play a crucial role in investigating the development and progression of AD. One widely used model in neuroscience studies is the free-living nematode Caenorhabditis elegans (C. elegans). The development of transgenic animals has allowed for the construction of the dvls2 (CL2006) C. elegans strain, which constitutively expresses the amyloid beta (Aβ) peptide. This study conducted a proteomic analysis on the dvls2 (CL2006) strain. Also, a cross-species comparative analysis was performed using microarray data from AD patients to identify genes with ontology in the dvls2 (CL2006). A total of 543 proteins were found to be differentially regulated in the dvls2 (CL2006) strain. Furthermore, in the analysis of the human datasets, 397 upregulated and 767 downregulated genes were identified. The differentially expressed genes (DEGs) were analyzed in Ortholist to identify their orthologs in C. elegans. Then, the orthologous genes in the dvls2 (CL2006) model were compared to the proteomic data, resulting in the identification of 29 upregulated and 24 downregulated proteins (DEPs). Functional enrichment analysis of DEPs revealed terms related to pyruvate, glucose, and glutamate metabolism, in addition to binding activities to unfolded proteins and ligases, highlighting the upregulation of chaperone and ubiquitination-associated proteins. Protein-protein network (PPI) was performed for the human DEGs and DEPs of dvls2 (CL2006). Topological analyses of the networks were performed, revealing the following C. elegans hub proteins: EEF-2, ALH-13, ENOL-1, RPL-2, TPI-1, CTS-1, RPL-9, RPL-23, CCT-1, and RPS-8. eEF-2 was identified as a key regulator of the human AD PPI and dvls2 (CL2006). Modules were analyzed in the networks, and the presence of key regulators was identified. This study provides the first proteomic characterization of the AD model dvls2 (CL2006) and a cross-species comparative analysis with data from AD individuals, supporting the use of dvls2 (CL2006) in AD studies.

RevDate: 2025-07-14

Zhang J, Wang C, Chang K, et al (2025)

A novel traditional Chinese medicine formula restores sleep and cognitive function in APP/PS1 mice by targeting glycolytic pathways and neuroinflammatory responses.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundAlzheimer's disease (AD) is recognized as a multifactorial neurodegenerative disorder involving numerous cellular and molecular processes, such as sleep disturbance, imbalance in brain glucose metabolism and neuroinflammation; these dysregulations typically precede the onset of symptoms. Hence, the results of mono-target therapy after AD diagnosis are in many cases unsatisfactory.ObjectiveTraditional Chinese medicine (TCM) presents significant potential for treating AD. Sleep disorders are one of the early symptoms of AD; however, there is no effective solution to sleep disorders caused by AD. Some TCMs have been shown to treat sleep disorders by regulating energy metabolism or improving neuroinflammation. This study aims to investigate if XX-F administrated in advance could alleviate AD by improving sleep quality and neuroinflammation.MethodsMice were given Xiexintongfu formula (XX-F) intragastrically for three months. Morris water maze and pentobarbital-induced sleep test were performed to evaluate cognition and sleep. Determine changes in energy metabolism related to glycolysis through western blot and specific assay kits. Using immunofluorescence and western blot to detect neuroinflammation.ResultsShortened sleep duration and cognitive impairment were observed in 6-month-old APP/PS1 mice. XX-F significantly prolonged sleep duration and rescued cognition. In addition, XX-F reduced the number of amyloid-β (Aβ) plaques and ameliorated neuroinflammation, and inhibited glycolysis by reducing pyruvate kinase M2 (PKM2) and lactate levels while rescuing adenosine triphosphate (ATP) deficiency.ConclusionsWe demonstrate that XX-F can improve sleep and cognition of AD mice by regulating energy metabolism and reducing neuroinflammation. This is a potential treatment method for AD and requires further in-depth research.

RevDate: 2025-07-14

Tahami Monfared AA, Hummel N, Kopiec A, et al (2025)

Integrating intangible costs into societal cost estimates of Alzheimer's disease.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundAlzheimer's disease (AD) is associated with considerable economic burden, the full extent of which can be challenging to quantify from a societal perspective.ObjectiveTo estimate the total societal cost of AD in the United States by integrating direct costs, out-of-pocket expenses, indirect costs to caregivers, costs to business, and intangible/emotional costs to patients/caregivers across the disease continuum from mild cognitive impairment (MCI) to severe AD.MethodsIntangible costs were derived from a patient-caregiver survey. Other indirect costs were from a Health and Retirement Study (HRS) analysis; direct costs were from the literature. We estimated integrated societal cost per patient per month (PPPM) for MCI and AD (mild/moderate/severe). Negative binomial regression of indirect costs examined associations with severity, adjusting for baseline characteristics.ResultsIntegrated societal costs PPPM were $4176 for MCI and $7873 for AD ($6,634, $7,291, and $9287 for mild, moderate, and severe, respectively); intangible costs represented 24-32% of societal costs. Indirect costs were higher with AD versus MCI (p < 0.001); married status and nursing home residence were associated with lower indirect costs in AD.ConclusionsIntangible costs are a major driver, besides direct costs, of the integrated societal cost of MCI/AD. Societal costs are higher with more severe AD.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Outeiro TF, TCRG Vieira (2025)

Preface to the Special Issue "History, Biology and Pathobiology of Prions: A Field of Renewed Hopes".

Journal of neurochemistry, 169(7):e70156.

Research in the field of prion diseases has not only shed light on the mechanisms underlying transmissible spongiform encephalopathies (TSEs) but has also influenced the broader understanding of protein misfolding disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and other tauopathies and synucleinopathies. Although prion diseases are rare and invariably fatal, they have provided an invaluable conceptual framework for the study of age-associated neurodegenerative disorders. On the occasion of the "Prion 2023" meeting in Faro, Portugal, which brought together leading experts in prion biology and neurodegeneration to discuss emerging data and evolving concepts, we put together a special issue on the topic to discuss new structural insights, diagnostic technologies, and the increasing recognition of prion-like mechanisms in a wide range of proteinopathies. This Special Issue features six comprehensive review articles that highlight key advances and ongoing challenges in the study of prions and related disorders.

RevDate: 2025-07-13
CmpDate: 2025-07-13

Liu S, Cho M, Huang YN, et al (2025)

Multi-omics analysis for identifying cell-type-specific and bulk-level druggable targets in Alzheimer's disease.

Journal of translational medicine, 23(1):788.

BACKGROUND: Analyzing disease-linked genetic variants via expression quantitative trait loci (eQTLs) helps identify potential disease-causing genes. Previous research prioritized genes by integrating Genome-Wide Association Study (GWAS) results with tissue-level eQTLs. Recent studies have explored brain cell type-specific eQTLs, but a systematic analysis across multiple Alzheimer's disease (AD) genome-wide association study (GWAS) datasets or comparisons between tissue-level and cell type-specific effects remain limited. Here, we integrated brain cell type-level and bulk-level eQTL datasets with AD GWAS datasets to identify potential causal genes.

METHODS: We used Summary Data-Based Mendelian Randomization (SMR) and Bayesian Colocalization (COLOC) to integrate AD GWAS summary statistics with eQTLs datasets. Combining data from five AD GWAS, two single-cell eQTL datasets, and one bulk eQTL dataset, we identified novel candidate causal genes and further confirmed known ones. We investigated gene regulation through enhancer activity using H3K27ac and ATAC-seq data, performed protein-protein interaction (PPI) and pathway enrichment, and conducted a drug/compound enrichment analysis with Drug Signatures Database (DSigDB) to support drug repurposing for AD.

RESULTS: We identified 28 candidate causal genes for AD, of which 12 were uniquely detected at the cell-type level, 9 were exclusive to the bulk level and 7 detected in both. Among the 19 cell-type level candidate causal genes, microglia contributed the highest number of candidate genes, followed by excitatory neurons, astrocytes, inhibitory neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs). PABPC1 emerged as a novel candidate causal gene in astrocytes. We generated PPI networks for the candidate causal genes and found that pathways such as membrane organization, cell migration, and ERK1/2 and PI3K/AKT signaling were enriched. The AD-risk variant associated with candidate causal gene PABPC1 is located near or within enhancers only active in astrocytes. We classified the 28 genes into three drug tiers and identified druggable interactions, with imatinib mesylate emerging as a key candidate. A drug-target gene network was created to explore potential drug targets for AD.

CONCLUSIONS: We systematically prioritized AD candidate causal genes based on cell type-level and bulk level molecular evidence. The integrative approach enhances our understanding of molecular mechanisms of AD-related genetic variants and facilitates interpretation of AD GWAS results.

RevDate: 2025-07-14

Choudhary AJ, Mahajan SS, AS Majumdar (2024)

Nose to brain delivery of flurbiprofen from a solid lipid nanoparticles-based thermosensitive in-situ gel.

Neuroscience applied.., 3:104062.

Flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), has selective amyloid-lowering characteristics and can be utilized for Alzheimer's disease treatment. Oral flurbiprofen has poor brain bioavailability and high dose-related gastrointestinal adverse effects. To overcome these issues, the study aimed to formulate intranasal flurbiprofen solid lipid nanoparticles (SLN) based thermosensitive in-situ gel. SLN were formulated by the High-speed homogenization method. A 2[3] factorial design technique was utilized for optimization, wherein the influence of two independent variables, critical process parameters (X1 = surfactant concentration, X2 = D:L ratio) on critical quality attributes (Y1 = particle size, Y2=Percent Drug Loading, Y3=Percent Entrapment Efficiency) was ascertained at three distinct levels. The optimized SLN were then prepared into an SLN-based intranasal thermosensitive in-situ gel with Poloxamer 188 P (1.2% w/v) and Poloxamer 407 P (18% w/v). The in-vitro flurbiprofen release study demonstrated a 100% release of flurbiprofen from the SLN-based thermosensitive in-situ gel at 6 h. The ex-vivo flurbiprofen release study revealed a complete release of flurbiprofen from the SLN-based thermosensitive in-situ gel at 8 h. In the in-vivo tests, the in-situ gel (2 mg/kg) administered intranasally in rats demonstrated nearly three times greater brain bioavailability (Cmax = 490.3 ng/ml) than the oral marketed formulation of flurbiprofen, Ansaid® (10 mg/kg) (Cmax = 145.1 ng/ml). The plasma concentration obtained with intranasal in-situ gel (Cmax = 2.5 μg/ml) was lower than the oral marketed formulation (Cmax = 3.4 μg/ml). The time necessary to establish the maximal flurbiprofen concentration (Tmax) in the brain was 2 and 0.5 h for oral and intranasal formulations, respectively. Hence, the intranasal formulation could achieve maximal drug concentration in the brain in less time. Thus, flurbiprofen SLN-based thermosensitive in-situ gel can be a potential encouraging safe, non-invasive, and efficacious replacement to oral formulations for achieving direct brain targeting through nose-to-brain drug delivery, thereby treating neuroinflammatory conditions like Alzheimer's disease.

RevDate: 2025-07-14

Vardheim EG, Toft A, Nielsen JE, et al (2023)

Cerebrospinal fluid ubiquitin as a biomarker for neurodegenerative diseases: A systematic review.

Neuroscience applied.., 2:102438.

Ubiquitin plays a vital role in neuronal proteostasis, as a major but often overlooked component of neurotoxic protein aggregates across neurodegenerative diseases. Although neuropathological changes can be present for years before clinical onset, early and accurate diagnosis remains an immense challenge in this disease category. The level of ubiquitin in cerebrospinal fluid (CSF) has been assessed as a biomarker for several disease entities. This systematic review compares current findings and evaluates the potential of CSF ubiquitin as a fluid biomarker. A systematic literature search identified studies comparing CSF ubiquitin levels between a control group and patients with one of the following diseases: Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), Lewy body dementia (DLB), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). All included studies were reviewed systematically by two independent authors. 171 studies were identified. A total of 17 studies met the eligibility criteria and were included. Nine out of 13 studies found a significant increase of CSF ubiquitin in AD patients compared with control groups. Correlations between CSF ubiquitin and other established biomarkers were demonstrated in seven studies. A single study was included for both HD and DLB respectively, each showing significantly higher CSF ubiquitin in patients compared to controls. In patients with PD, FTD or ALS, CSF ubiquitin levels were generally equal to those of the control groups, with two studies showing significantly decreased concentrations in a PD and an FTD cohort. Presently, the available body of research is insufficient to assess whether CSF ubiquitin could contribute to the clinical setting, alongside established markers of neurodegeneration. The correlation of elevated CSF ubiquitin with AD is well-founded, whilst validation of reduced or unchanged levels in the other neurodegenerative diseases will determine the usefulness of the biomarker in clinical practice.

RevDate: 2025-07-14

Knorr U, Simonsen AH, Engström ELS, et al (2023)

Associations between sleep quality and biomarkers for neurodegeneration - A longitudinal one-year case-control study of patients with bipolar disorder and healthy control individuals.

Neuroscience applied.., 2:101011.

Disturbed sleep during affective episodes may impact levels of cerebrospinal fluid (CSF)-amyloid-beta (Aβ)42 and other biomarkers of neurodegeneration in patients with bipolar disorder (BD). The study aimed to investigate the correlations between sleep and biomarkers for Alzheimer's disease (AD) and neurodegeneration in BD and healthy controls (HC). We present a prospective, longitudinal case-control study of euthymic patients with BD (N = 86) and HC (N = 44). All participants were evaluated with clinical assessments at baseline, and after a year. The patients' affective states were recorded weekly as euthymic, subthreshold level, major depression, or (hypo)mania. Patients were re-assessed during and after an episode if it occurred during follow-up. Total sleep scores based on three Hamilton-17 Depression Scale items were analyzed in relation to concentrations of CSF-Aβ42, CSF-Aβ40, CSF-Aβ38, CSF-Aβ42/40 and 42/38 ratios, CSF-soluble amyloid-precursor proteins α+β, plasma-Aβ42, plasma-Aβ40, CSF-phosphorylated-tau, CSF-total-tau, plasma-total-tau, CSF-neurofilament-light, plasma-neurofilament-light, CSF-neurogranin, serum-S100B, CSF-8-oxo-7,8-dihydro-guanosine, CSF-8-oxo-7,8-dihydro-2'-deoxyguanosine, urine-8-oxo-7,8-dihydro-guanosine, and urine-8-oxo-7,8-dihydro-2'-deoxyguanosine. The primary outcome was the association between total sleep scores and levels of CSF-Aβ42 at baseline and follow-up estimated by the regression coefficient in a linear mixed model. We found no statistically significant associations between sleep and CSF-Aβ42 (-2.307 pg/ml (95% CI: -9.525-4.911; p = 0.523)) or any other biomarkers. However, higher sleep scores appeared to be associated with higher CSF-Aβ42/40 and CSF-Aβ42/38 ratios, and lower CSF-total-tau concentration, but were not statistically significant after correction for multiple testing. In conclusion attenuated sleep during an affective episode was not associated with changes in biomarkers for AD and neurodegeneration in BD, but larger prospective studies are needed.

RevDate: 2025-07-13
CmpDate: 2025-07-13

Duan Y, Tang Y, Qi C, et al (2025)

Naturally occurring seco- and nor-polycyclic polyprenylated acylphloroglucinols: distribution, structural diversity, andbiological activity.

Chinese journal of natural medicines, 23(7):824-837.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) represent a distinct subclass of specialized metabolites predominantly found in the plant kingdom, particularly within the Guttiferae (Clusiaceae) family. These compounds exhibit remarkable structural diversity and a wide range of biological activities. Seco- and nor-PPAPs, two unique variants of PPAPs with diverse skeletal structures, have been extensively investigated. As of June 2023, 200 compounds have been isolated from four genera, with Hypericum being the primary source. Notably, 115 of these compounds were identified in the past four years, indicating a significant increase in research activity. Seco- and nor-PPAPs can be categorized into six main subgroups based on the original PPAP scaffolds. Biological studies have revealed their potential in various therapeutic applications, including anti-cancer, anti-inflammatory, hepatoprotective, anti-Alzheimer's disease (anti-AD), multidrug resistance (MDR) reversal, anti-depressant, neuroprotective, and immunosuppressive effects. This review provides a comprehensive overview of the occurrence, structures, and bioactivities of natural seco- and nor-PPAPs, offering valuable insights for the further development of PPAPs.

RevDate: 2025-07-13
CmpDate: 2025-07-13

De Vleeschouwer M, Pradhan B, Rousseau F, et al (2025)

Chemical Synthesis of Medin via a Removable Aggregation-Suppressing Linker.

Journal of peptide science : an official publication of the European Peptide Society, 31(8):e70041.

Medin, a 50-amino acid fragment derived from the protein MFG-E8 (lactadherin), is the most prevalent amyloid found in humans, present in the vasculature of nearly all individuals over the age of 50. Its biological relevance is highlighted by its co-localization with amyloid-β (Aβ) deposits in both Alzheimer's disease patients and transgenic mice models. Notably, Medin promotes amyloid-β aggregation, forming mixed fibrils with Aβ and enhancing its deposition in blood vessels. Here we report a new and efficient strategy to chemically access this compound. Our approach employs a solubilizing linker that not only ensures high solubility but also suppresses aggregation, allowing efficient purification of the product. The linker can be removed without a trace, after which the product behaves identically to wild-type Medin and forms amyloid fibrils. The synthesis route allows opening up a new chemical space, including nonnatural modifications like biotinylation. Together with the control over the aggregation properties, this is a powerful tool for amyloid protein studies.

RevDate: 2025-07-13

Zhu F, Yang R, He B, et al (2025)

Neuroregulatory effect of royal jelly.

The Journal of nutritional biochemistry pii:S0955-2863(25)00191-3 [Epub ahead of print].

Royal jelly (RJ), a nutrient-rich secretion fed exclusively to queen honeybees, exhibits diverse biological activities. Due to limited insights into its effects on central nervous system (CNS)-related functions and pathologies, this review attempts to recapitalize the recent advances of neuroregulatory function of RJ in mammals and humans. Another central aim of this review is to summarize the known mechanisms underlying the neuroregulatory effect of RJ. RJ components were first discussed concerning their link to neuroprotection, with a focus on the queen bee acid (QBA, 10-HDA, trans-10-hydroxy-2-decenoic acid), MRJPs (major royal jelly proteins), and microbiota. The neuroregulatory implications of RJ are then categorized into three domains: fundamental CNS functions, including learning and memory, in vitro neuronal cell activity and social behavior; neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), anxiety and depression; neurotoxic events. In terms of mechanistic insights, RJ modulates neuroinflammation, a pivotal driver of neurological disorders, and acts as an HDAC (histone deacetylase) inhibitor among other epigenetic regulators, influencing gene expression in the CNS. Emerging evidence also implicates the microbiota-gut-brain (MGB) axis, where RJ alters gut microbiota composition, subsequently impacting brain function. Finally, we outline critical research directions, including clinical significance, comparisons with other honeybee products, epigenetic mechanisms, and RJ's untapped role in reshaping social behaviors. This review aims to consolidate our knowledge on the neuroregulatory effects of RJ, underscoring its therapeutic potential for neurological conditions in both nutritional and pharmaceutical contexts.

RevDate: 2025-07-13

Varga K, Sikur N, Paszternák A, et al (2025)

Resveratrol Restores Insulin Signaling and Balances Mitochondrial Biogenesis and Autophagy in Streptozotocin-Induced Neurodegeneration in vitro.

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences pii:S0928-0987(25)00201-5 [Epub ahead of print].

Resveratrol, a natural phytoalexin, has been suggested to have beneficial effects in age-related diseases, including Alzheimer's disease. Studies indicate that it may delay memory decline and exert neuroprotective properties in vitro and in vivo. However, the precise mechanisms underlying these effects remain unclear, and the impact of resveratrol on central insulin resistance-a key feature of neurodegenerative disorders-remains insufficiently explored. Given the potential therapeutic significance of targeting insulin sensitivity in neurodegeneration, further investigation into the role of resveratrol in modulating these pathways is warranted. Our aim was to investigate the effects of resveratrol on insulin signaling and mitochondrial function in a previously established streptozotocin-induced in vitro neurodegeneration model. The phosphorylation status of key insulin signaling proteins and regulators of insulin resistance and autophagy markers were analyzed via Western blot and an ELISA-based microarray technique. The effects of resveratrol on mitochondrial biogenesis were evaluated through Mitotracker staining and quantification of mitochondrial mRNA and protein expression. Resveratrol augmented the cytoprotective effect of insulin in a concentration-dependent manner. It reduced the Ser(312) phosphorylation of IRS1, which is commonly linked to insulin resistance, and lowered the IC50 value for Tyr(895) phosphorylation required for activation. Similar insulin-sensitizing effects were observed in downstream signaling components. Resveratrol treatment exerted a caloric restriction mimetic activity through activating the AMPK/PGC1α/SIRT1 pathway and upregulated the expression of mitochondrial transcription factor TFAM and ATP synthase subunit (ATP5B). Despite the activation of mitochondrial biogenesis, the number of mitochondria was not altered, because it simultaneously induced autophagy marked by ULK1 phoshorylation and LC3 lipidation. Our findings indicate that resveratrol can enhance insulin signaling, even at the initial step of IRS1 phosphorylation. Its insulin-sensitizing effects extend beyond metabolic regulation to include survival responses. Resveratrol as a caloric restriction mimetic exerted a balanced effect on mitochondrial biogenesis and autophagy therefore improving mitochondrial quality control.

RevDate: 2025-07-13

Giannelli S, Eroli F, Loera-Valencia R, et al (2025)

Elevated 24-hydroxycholesterol levels counteract okadaic acid-induced tau hyperphosphorylation and neuronal morphology impairment.

Neurobiology of disease pii:S0969-9961(25)00245-1 [Epub ahead of print].

Multiple findings underline a link between altered brain cholesterol metabolism and Alzheimer's disease (AD) pathogenesis. Physiologically, excess brain cholesterol is mainly converted into 24-hydroxycholesterol (24-OHC) by the neuron-specific enzyme CYP46A1. Of note, we previously observed in autopsy specimens from human AD brains that 24-OHC and, in parallel, CYP46A1 expression decreases at advanced stages, suggesting a possible cause-effect between these reductions and AD progression. In the present study, we aimed to investigate whether maintaining high levels of 24-OHC, by its exogenous administration or CYP46A1 overexpression, can counteract tau hyperphosphorylation and accumulation of prefibrillar tau oligomers. To create an AD-like in vitro model exhibiting tauopathy, we utilized okadaic acid (OKA), a chemical compound that induces tau hyperphosphorylation. Our data show that in 24-OHC-treated primary neurons derived from wild type mice, and in neurons from CYP46A1 overexpressing mice (CYP46Tg), elevated oxysterol levels effectively prevented tau hyperphosphorylation and oligomerization. Furthermore, the dendritic arborization decrease induced by OKA was prevented, maintaining the organization and stability of the neuronal cytoskeleton. While hypothesized underlying molecular mechanisms (GSK3β, CDK5, ERK1/2, and PP2A) seem not to be involved, the protective effect of 24-OHC remains evident. The data highlight the positive effects of 24-OHC and the need to prevent its reduction in the brain. This can be achieved either through the exogenous administration of 24-OHC using suitable technologies or by maintaining elevated levels and the activity of the enzyme CYP46A1. These therapeutic approaches could be useful to prevent or slow AD progression.

RevDate: 2025-07-13

Brüge A, Ponimaskin E, J Labus (2025)

Targeting the serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges.

Pharmacological reviews, 77(5):100071 pii:S0031-6997(25)07479-4 [Epub ahead of print].

More than 65 million people worldwide experience neurodegenerative diseases, such as Alzheimer disease, frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis. As the risk of developing these diseases increases with age, increasing life expectancy will further accelerate their prevalence. Despite major advances in the understanding of the molecular mechanisms of neurodegeneration, no curative therapy is available to date. Neurodegenerative diseases are known to be associated with alterations in serotonergic neurotransmission, which might critically contribute to the pathogenesis of these diseases. Therefore, targeting the serotonergic system appears to be a promising therapeutic approach. In this review, we provide a comprehensive overview of pathological changes in serotonergic neurotransmission in different neurodegenerative diseases and discuss novel treatment strategies based on targeted modulation of the serotonergic system. We primarily focus on the therapeutic approaches modulating serotonin homeostasis, its biosynthesis, and the modulation of defined serotonin receptors. SIGNIFICANCE STATEMENT: A common feature of multiple neurodegenerative diseases is dysregulation of the serotonergic system at the cellular, molecular, and genetic levels that strongly contributes to specific pathological phenotypes. Targeting these alterations represents a suitable therapeutic strategy to combat disease-relevant pathomechanisms, slow down disease progression, and overcome pathological consequences.

RevDate: 2025-07-13

Li X, Li Z, Chen H, et al (2025)

Unraveling APOE4: The dual role in CNS and peripheral inflammation in Alzheimer's disease.

International immunopharmacology, 163:115199 pii:S1567-5769(25)01189-0 [Epub ahead of print].

Inflammation in both CNS and peripheral circulation system is known to have a significant impact in AD pathogenesis. In the CNS, AD-related inflammation involves the activation of various types of immune cells, such as microglia, astrocytes, and T cells. Meanwhile, one of the hallmarks of peripheral circulation inflammation in AD is activation of T cells. In addition, Apolipoprotein E4 (APOE4), as a key genetic risk factor for late-onset AD, significantly influences both CNS and peripheral circulation system inflammation in the pathogenesis of AD. Moreover, APOE4 play a key role in various pathological changes in AD, such as Aβ accumulation, tau phosphorylation, lipid metabolism disorders, and BBB dysfunction, resulting in microglia, astrocytes, and T cells activation, as well as the release of inflammatory factors. This comprehensive review aims to elucidate the specific mechanisms through which APOE4 triggers inflammation in both CNS and peripheral circulation system in the context of AD. Furthermore, we also summarize several therapeutic approaches that target APOE for the treatment of AD.

RevDate: 2025-07-13
CmpDate: 2025-07-13

de Oliveira AP, Baghel D, Holcombe B, et al (2025)

Lipid mediated formation of antiparallel aggregates in cerebral amyloid angiopathy.

Acta neuropathologica, 150(1):3.

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder marked by amyloid-β (Aβ) deposition in blood vessel walls, leading to hemorrhage and recurring stroke. Despite significant overlap with Alzheimer's disease (AD) through shared Aβ pathology, the specific structural characteristics of Aβ aggregates in CAA and their variations between stages of disease severity are yet to be fully understood. Traditional approaches relying on brain-derived fibrils can potentially overlook the polymorphic heterogeneity and chemical associations within vascular amyloids. This study utilizes sub-diffraction, label-free optical photothermal infrared (O-PTIR) spectroscopic imaging to directly probe the chemical structure and heterogeneity of vascular amyloid aggregates within human brain tissues across different CAA stages. Our results demonstrate a clear increase in β-sheet content within vascular Aβ deposits corresponding to disease progression. Crucially, we identify a significant presence of antiparallel β-sheet structures, particularly prevalent in moderate/severe CAA. The abundance of antiparallel structures correlates strongly with co-localized lipids, implicating a lipid-mediated aggregation mechanism. We substantiate the ex-vivo observations using nanoscale AFM-IR spectroscopy and demonstrate that Aβ40 aggregated in-vitro with brain-derived lipids adopts antiparallel structural distributions mirroring those found in CAA vascular lesions. This work provides critical insights into the structural distributions of Aβ aggregates in CAA, highlighting the presence of polymorphs typically associated with transient intermediates, which may lead to alternate mechanisms for neurotoxicity.

RevDate: 2025-07-13

Lu J, Qiu Y, Zhao C, et al (2025)

Synthesis and multi-target evaluation of 2-(2-phenylethyl)/2,3-styrylchromone derivatives as potential anti-Alzheimer's disease agents.

Molecular diversity [Epub ahead of print].

A series of novel 2-(2-phenylethyl)chromone and 2/3-styrylchromone derivatives (A1-A16, B1-B43) were designed, synthesized, and systematically evaluated for their multi-target activities against key pathological factors of Alzheimer's disease (AD). In vitro studies demonstrated that compound B22 exhibited potent and selective acetylcholinesterase (AChE) inhibition (IC50 = 2.52 ± 1.11 μM) with negligible activity against butyrylcholinesterase (BuChE) (IC50 > 500 μM), along with strong monoamine oxidase-B (MAO-B) inhibition (93.6% inhibition at 1 μM). Thioflavin T (ThT) fluorescence assays revealed that B18 and B22 effectively inhibited the aggregation of both Aβ40/42 peptides (IC50 = 1.44 and 1.00 μM, respectively) and Tau fibrillization (IC50 = 2.61 and 3.32 μM), while promoting the disaggregation of pre-formed amyloid fibrils. Molecular docking and molecular dynamics (MD) simulations indicated that B22 exhibited favorable binding affinities (ΔG ≈ - 7.3 kcal/mol) and stable interactions within the AChE active site. Furthermore, B22 significantly attenuated reactive oxygen species (ROS) levels (by up to 89.5%) and rescued Aβ-induced cytotoxicity in SHSY5Y cells, restoring cell viability to 85.7% at 20 μM. Collectively, these results highlight chromone-based scaffolds, particularly compound B22, as promising multifunctional candidates for the development of disease-modifying therapeutics targeting AD.

RevDate: 2025-07-12
CmpDate: 2025-07-12

Kawai Y, Kuriyama M, Sohma Y, et al (2025)

The dynamics of oxygenation to Aβ fibrils using an azobenzene-boron complex type photocatalyst and light energy.

Scientific reports, 15(1):25241.

Alzheimer disease (AD) is characterized by the deposition of amyloid fibrils, such as senile plaques, composed of amyloid β peptide (Aβ). As a novel therapeutic modality, we have previously developed an azobenzene-boron complex type photocatalyst that photo-oxygenates Aβ fibrils. And the in vivo photo-oxygenation reaction using this photocatalyst successfully reduced the Aβ fibrils in the brain. Since Aβ fibril is one of the causative molecules in the brains of AD patients, the photocatalyst is expected to be a new modality for disease-modifying therapy against AD. However, the exact relationship between light energy and photo-oxygenating activity for Aβ fibrils remains unclear. In this paper, we have demonstrated using mass spectrometric analysis that the number of oxygens added to Aβ fibrils was increased in a sigmoidal curve with the logarithm of light energy. We also showed that it depended on the total light energy, not on the irradiance. These data suggest that photo-oxygenation proceeds at even lower levels of light energy, and it may be possible to induce photo-oxygenation in areas where light penetration is difficult, such as the human brain.

RevDate: 2025-07-12
CmpDate: 2025-07-12

Blake M, Brown DC, Chen C, et al (2025)

A combined naturalistic driving, clinical, and neurobehavioral data set for investigating aging and dementia.

Scientific data, 12(1):1209.

Alzheimer's disease and related dementia (ADRD) are becoming increasingly prevalent and are predicted to affect up to 153 million globally by 2050. Outside of biomarkers that measure pathology, there is a lack of methods to quantify and study complex behaviors such as driving and managing finances that precede cognitive decline among older adults. The DRIVES Project at Washington University School of Medicine has developed a pipeline to measure naturalistic driving behavior of older adult drivers enrolled in longitudinal studies of aging and ADRD. This driving behavior is captured in the form of tabular data for each trip a participant takes and is processed in two formats: low-frequency driving data, comprising approximately 2.8 million trips (37 GB), and high-frequency driving data, with approximately 1.4 million trips (2.6 TB). This pipeline also captures common participant sociodemographic characteristics, clinical features, and environmental context across various weather conditions, as well as the Area Deprivation Index and the Social Vulnerability Index, to comprehensively characterize the multidimensional nature of neurodegenerative processes among older adults.

RevDate: 2025-07-12

Mak E, Reid RI, Przybelski SA, et al (2025)

Author Correction: Cortical microstructural abnormalities in dementia with Lewy bodies and their associations with Alzheimer's disease copathologies.

NPJ Parkinson's disease, 11(1):209 pii:10.1038/s41531-025-01068-y.

RevDate: 2025-07-12

Bariviera JL, Ribeiro LR, Furian AF, et al (2025)

Effects of Intranasal Antibodies on Murine Models of Neurological Disorders: A Systematic Review.

European journal of pharmacology pii:S0014-2999(25)00694-6 [Epub ahead of print].

Neurological disorders significantly impact billions of individuals worldwide, representing a leading cause of disability and premature death. Antibody-based therapeutics, known for their high target specificity, have been investigated for various neurological disorders, including Alzheimer's and Parkinson's diseases. However, despite advancements in neuropharmacology, the use of therapeutic antibodies in neurological disorders faces considerable challenges, particularly due to their limited bioavailability across the blood-brain barrier and often invasive administration protocols. In this context, the intranasal route has emerged as a promising noninvasive alternative for drug delivery, prompting direct brain access and rapid therapeutic effects, especially for larger molecules such as antibodies. Therefore, we aimed at the present study to gather information on the current state of research in the field and to summarize potential trends in methodology employed in such studies. The present systematic review identified a total of 1,135 articles through databases such as Scopus, Web of Science, and PubMed, ultimately including 31 articles for detailed analysis. The study methodology was preregistered at Open Science Framework platform. Our findings indicate that Alzheimer's disease is the most studied condition, and the hippocampus is the most frequently evaluated brain area. Monoclonal antibodies were the predominant therapeutic agents utilized, and significant variation in dosages used were noted. Furthermore, despite being high-molecular entities, antibodies can target both intracellular and extracellular proteins and eventually bring neuroprotective effects after intranasal administration. In summary, while this systematic review highlights the potential of intranasal antibodies for treating neurodegenerative diseases, there is significant room for additional studies on their mechanisms of action, long-term effects, and strategies to clinical translation.

RevDate: 2025-07-12

Zhang Z, Xue X, Liu P, et al (2025)

The Role of Photobiomodulation in Modulating Neural Activity and Brain Function: A Systematic Bibliometric Analysis.

Photodiagnosis and photodynamic therapy pii:S1572-1000(25)00244-3 [Epub ahead of print].

This systematic bibliometric analysis evaluates the scientific evidence, impact, and trends of photobiomodulation (PBM) for central nervous system (CNS) disorders. Analyzing 150 relevant PubMed-indexed studies (including 46 clinical trials) up to September 2024, we demonstrate PBM's positive effects on the CNS. Key mechanisms include enhanced ATP synthesis, modulated nitric oxide signaling, improved neuronal excitability, suppressed oxidative stress, anti-inflammatory effects, and ion channel modulation. PBM offers therapeutic flexibility: shorter-wavelength, high-irradiance power lasers effectively target deep brain structures, while both modalities suit superficial cortical applications where fine spatial control is nonessential.Crucially, PBM induces long-lasting biological effects, highlighting significant potential for chronic CNS conditions like Alzheimer's disease, Parkinson's disease, and stroke. However, critical challenges hinder translation: optimizing disease-specific wavelengths and light sources (laser vs. LED, continuous vs. pulsed), and establishing standardized, long-term treatment protocols based on robust dose-response relationships. Resolving heterogeneity in parameters (energy density, power, potential thermal effects) is paramount for PBM to become a reliable neuromodulation tool. This analysis provides critical insights for advancing targeted PBM therapies in CNS.

RevDate: 2025-07-12

Azmal M, Paul JK, Prima FS, et al (2025)

Microglial dysfunction in Alzheimer's disease: Mechanisms, emerging therapies, and future directions.

Experimental neurology pii:S0014-4886(25)00238-9 [Epub ahead of print].

Alzheimer's disease (AD) is a severe neurodegenerative condition characterized by progressive cognitive decline and behavioral changes. These symptoms are primarily driven by the accumulation of amyloid-beta (Aβ) plaques, tau tangles, and persistent neuroinflammation. Microglia, the brain's resident immune cells, play a crucial role in the disease's progression. Initially, these cells protectively respond to Aβ deposits, working to clear plaques and support neuronal health. However, prolonged activation of microglia leads to a transition from a neuroprotective state to a pro-inflammatory one, ultimately contributing to neuronal damage and worsening disease progression. This review explores the molecular mechanisms responsible for microglial dysfunction in AD, with a particular emphasis on key inflammatory pathways, including NF-κB, MAPK, and TLR4 signaling. These pathways drive the release of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, which further amplify neuroinflammation, disrupt synaptic plasticity, and contribute to neuronal loss. Additionally, emerging therapeutic strategies aimed at modulating microglial activity to reduce neuroinflammation and enhance Aβ clearance are examined. A key focus is placed on the future of AD research, emphasizing the importance of longitudinal studies to gain a deeper understanding of how microglia contribute to disease progression over time. The review also highlights the potential of personalized medicine, which seeks to tailor treatments based on an individual's unique genetic and environmental risk factors. Notably, genetic predispositions such as the APOE4 allele, along with environmental influences like air pollution and chronic infections, are identified as significant modulators of microglial activity. Given the complexity of AD, a comprehensive, multi-faceted approach will be essential for advancing research and developing more effective therapeutic interventions.

RevDate: 2025-07-12

Kang X, Tian J, Shu Q, et al (2025)

Microglia-neuron crosstalk in Alzheimer's disease: an exploration of molecular mechanisms and pathological implications.

Neuroscience pii:S0306-4522(25)00781-X [Epub ahead of print].

Microglia, the resident immune sentinels of the central nervous system (CNS), engage in dynamic crosstalk with neurons, the principal units of information transmission, to maintain CNS homeostasis. Emerging research has established that dysregulation of this intricate communication network critically contributes to Alzheimer's disease (AD) pathogenesis, offering novel insights for therapeutic development. In this review, we dissect molecular mechanisms underlying multifaceted microglia-neuron interactions in AD. Bidirectional communication occurs through neurotransmitter transmission, synaptic elimination, the secretion of signaling molecules and extracellular vesicles, and direct membrane contact. Disrupted crosstalk in AD triggers pathogenic cascades: cholinergic dysfunction induces microglial hyperactivation and oxidative stress; aberrant synaptic elimination accelerates memory loss; and neuron-derived pathological vesicles propagate neuroinflammation. Elucidating these interactions reveals promising therapeutic insights for AD. Targeting crosstalk pathways-such as activating TREM2, selectively inhibiting the complement cascade, or modulating inflammasome activity-may halt neurodegeneration while preserving essential immune surveillance. Moreover, integrating spatiotemporal omics with live imaging could dynamically track microglia-neuron crosstalk, revealing critical transition points from neuroprotection to neurodegeneration.

RevDate: 2025-07-12

Ding Z, Zhuang Y, Jian J, et al (2025)

yeThe Role of BMAL1 in Glial Cells: Implications for Cognitive Function in Neurodegenerative Diseases.

Brain research bulletin pii:S0361-9230(25)00275-8 [Epub ahead of print].

Disruption of the circadian rhythm may precede the typical clinical symptoms of neurodegenerative diseases and is a potential risk factor for Alzheimer's disease (AD), associated dementias, and Parkinson's disease (PD). The morphology and function of mammalian glial cells and their gene expression correlate with circadian rhythms. Brain and muscle Arnt-like protein-1(BMAL1) is a core player in the functional regulation of glial cells and is a major regulator of circadian rhythms. According to new research, neuroglial BMAL1 is implicated in several pathological processes, including altered energy metabolism, dysregulated protein homeostasis, decreased synaptic plasticity, disrupted myelin formation and regeneration, and neuroinflammation, which are correlated with cognitive impairment in neurodegenerative diseases. To provide concepts and perspectives for precision medicine of the disease, we have systematically summarized the mechanism of action of neuroglial BMAL1 in cognitive impairment in neurodegenerative diseases and related studies, established a signaling network map between neuroglial BMAL1 and cognitive impairment, and discussed therapeutic strategies targeting neuroglial BMAL1.

RevDate: 2025-07-12

Zhang H, W Wu (2025)

Leveraging AI to Optimize Galectin-3 Inhibitors for Alzheimer's Disease: how to move forwards.

RevDate: 2025-07-12

Bershteyn M, Zhou H, Fuentealba L, et al (2025)

Human stem cell-derived GABAergic interneuron development reveals early emergence of subtype diversity and gradual electrochemical maturation.

Neuron pii:S0896-6273(25)00468-4 [Epub ahead of print].

Medial ganglionic eminence-derived inhibitory γ-aminobutyric acid (GABAergic) pallial interneurons (MGE-pINs) are essential regulators of cortical circuits, and their dysfunction is associated with neurological disorders. We developed human MGE-pINs from pluripotent stem cells for the treatment of drug-resistant epilepsy. Here, we analyzed xenografted MGE-pINs from human pluripotent stem cells (hMGE-pINs) over the lifespan of host mice in healthy and epileptic environments using single-nuclei RNA sequencing. Comparative transcriptomics against endogenous human brain datasets revealed that 97% of grafted cells developed into somatostatin (SST) and parvalbumin (PVALB) subtypes, including populations that exhibit selective vulnerability in Alzheimer's disease. Transplanted hMGE-pINs demonstrated rapid emergence of subclass features, progressing through distinct transcriptional states sequentially involving neuronal migration, synapse organization, and membrane maturation. We present molecular, electrophysiological, and morphological data that collectively confirm the derivation of diverse bona fide human SST and PVALB subtypes, providing a high-fidelity model to study hMGE-pIN development as well as a compositional atlas for regenerative cell therapy applications.

RevDate: 2025-07-12

Kew CL, Han G, Holland A, et al (2025)

Risk profiles of Alzheimer's disease and related dementias care partners: A latent profile analysis to inform intervention.

Geriatric nursing (New York, N.Y.), 65:103462 pii:S0197-4572(25)00305-2 [Epub ahead of print].

OBJECTIVES: Identify risk factors for profiles of caregiver burden, depression, and social disconnectedness among Alzheimer's disease and related dementias (ADRD) care partners.

METHODS: Latent Profile Analysis of baseline caregiver burden, depressive symptoms, and social disconnectedness among 95 ADRD care partners enrolled in a problem-solving intervention clinical trial. Multivariable linear regressions determined risk factors associated with these profiles. Intervention engagement was compared between profiles.

RESULTS: The Lower Distress group (n = 56) was characterized by lower burden, depressive symptoms, and disconnectedness compared to the Higher Distress group (n = 39). Lower Distress was associated with higher life satisfaction (p = 0.019), more social support (p = 0.022), and less resentment towards caregiving (p < 0.001) than Higher Distress. Both groups had similar intervention attendance (median = 100 %) and engagement (median = 5 and 5.1 of 6).

CONCLUSION: Two profiles differed by well-being and social dynamics, but intervention engagement was similar. Multifaceted approaches are needed to improve health and well-being among ADRD care partners.

RevDate: 2025-07-12

D C, M M (2025)

Fusion of bio-inspired optimization and machine learning for Alzheimer's biomarker analysis.

Computers in biology and medicine, 196(Pt A):110746 pii:S0010-4825(25)01097-2 [Epub ahead of print].

Identification of Alzheimer's Disease (AD), especially in its early phases, presents significant challenges due to the nonexistence of reliable biomarkers and effective treatments. Clinical trials for AD medications also suffer from high failure rates. Accurate diagnosis, prognosis determination, progression monitoring, and treatment effect assessment depend heavily on analysing various brain regions, including the Corpus Callosum (CC), Grey Matter (GM), Hippocampus (HC), Ventricle, and White Matter (WM). Among these, the Hippocampus plays a pivotal role in early detection. This study employs deep learning for classification and optimization techniques for segmenting the HC region to enable the AD diagnosis. The pre-processing of raw images involves histogram equalization and Otsu's thresholding methods. The research focuses on data collection and pre-processing as essential steps for advancing diagnostic methods. Segmentation and classification utilize Elephant Herding Optimization (EHO) and Crow Search Optimization (CSO) techniques in combination with the ResNet50 classifier. The results reveal that Crow Search Optimization achieves superior performance, with an accuracy of 92 %, surpassing Elephant Herding Optimization.

RevDate: 2025-07-12

Aydemi̇r M, Gacar G, Halbutoğullari ZS, et al (2025)

Adipose tissue-derived mesenchymal stem cell extracellular vesicles enhance amyloid-beta degradation in an in vitro Alzheimer's model.

Tissue & cell, 96:103035 pii:S0040-8166(25)00315-5 [Epub ahead of print].

OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder lacking effective treatment. Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) have shown promise in degrading amyloid beta (Aβ) plaques due to their low immunogenicity and ability to mediate intercellular communication. This study investigates the therapeutic potential of EVs derived from human adipose tissue MSCs (hAT-MSCs) and preconditioned human adipose tissue MSCs in an in vitro AD model.

METHODS: MSCs characterized by flow cytometry and differentiation assays. hAT-MSCs stimulated with hydrogen peroxide (H₂O₂) or a cytokine complex (CC; TNF-α, IL-1β, IFN-γ). EVs were isolated via ultracentrifugation and analyzed by electron microscopy and Zetasizer. An in vitro AD model was established using neural-differentiated SH-SY5Y cells treated with Aβ peptides. Differentiation and Aβ degradation were assessed using immunocytochemistry, qRT-PCR, and ELISA.

RESULTS: EVs derived from cytokine complex stimulated hAT-MSCs significantly reduced Aβ plaque size and intensity compared to EVs from unstimulated or H₂O₂-stimulated cells. When immunocytochemistry images were analyzed using ImageJ, Aβ levels were found to be highest in the Alzheimer's group and lowest in the CC-EV group. According to ELISA analyses, no significant difference was observed between the Alzheimer's model (a1) and the hAT-MSC-EVs (a3) groups, whereas both the H₂O₂-EV (a4) and CC-EV (a5) groups showed a significant reduction compared to the control (**** P ≤ 0,0001) CONCLUSION: These findings suggest that cytokine-stimulated hAT-MSC-derived EVs effectively promote Aβ degradation and represent a promising cell-free therapeutic strategy for AD.

RevDate: 2025-07-12
CmpDate: 2025-07-12

Sil M, Mukherjee N, Chatterjee I, et al (2025)

Glial Cells in Alzheimer's Disease: Pathogenic Mechanisms and Therapeutic Frontiers.

Journal of molecular neuroscience : MN, 75(3):87.

The rising incidence of brain diseases parallels the global trend of an aging population, with Alzheimer's disease (AD) being a leading neurodegenerative disorder characterized by memory loss, dementia, and cognitive decline. Despite extensive research, current treatments for AD remain largely symptomatic and have had limited success in halting disease progression, thereby shifting attention toward glial cells as promising therapeutic targets due to their emerging roles in AD pathogenesis. Astrocytes are involved in both beneficial and pathological processes in AD, such as cytokine secretion, Aβ removal, metabolic support, and tau pathology, with deficiency resulting in neuroinflammation and excitotoxicity. Microglia have dual functions in AD by phagocytosing amyloid plaques and limiting tau spread in initial phases but may develop a pro-inflammatory, neurodegenerative phenotype with progression of the disease. Oligodendrocytes and their precursors are involved in Aβ generation and myelin homeostasis, and their disturbance is responsible for white matter lesions and cognitive impairment, though their exact mechanisms are less clear. This review also examines emerging therapeutic strategies targeting glial cells, including modulating TREM2 pathways and novel drug candidates. These methods highlight the therapeutic value of the glial cells and provide valuable leads for furthering the treatment of AD by elucidating their changing roles in the course of the disease.

RevDate: 2025-07-12

Deepika , Thakur A, Panghal A, et al (2025)

Crosstalk between copper, Alzheimer's disease, and melatonin.

Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine [Epub ahead of print].

Alzheimer's disease (AD) is a neurodegenerative disorder that causes cognitive impairment and loss of neurons. According to the Alzheimer's Association's 2022 US report, the USA saw a 145% increase in AD-related fatalities from 2000 to 2020, with an estimated financial burden of these disorders surpassing $1 trillion annually. Its pathological features include neurofibrillary tangles and amyloid-beta (Aβ) plaques. Although there is presently no treatment that may stop the growth of AD, new clinical trials have suggested that anti-amyloid disease-modifying drugs may reduce the progression of the illness. According to a recent study, Copper (Cu) dysregulation plays a crucial role in AD pathogenesis by causing oxidative stress and encouraging the aggregation of Aβ. Meanwhile, melatonin, a neurohormone with strong neuroprotective, antioxidant, and Cu chelation qualities, has drawn an interest due to its possible use for AD treatment. This review thoroughly summarizes the most recent research, including in vivo, in vitro, and human studies, and also examines the complex relationships among AD, melatonin, and Cu toxicity. We observe how an excess of Cu aggravates AD pathogenesis and how the special qualities of melatonin can counteract these effects. Melatonin is a promising molecule having a dual approach to address pathogenesis of AD by chelating excess Cu and lowering oxidative stress. Comprehending the interplay between Cu dysregulation and the protective mechanisms of melatonin may result in innovative therapies, providing promises for enhanced management of AD.

RevDate: 2025-07-12

Maiti P, Manna J, Burch ZN, et al (2025)

RETRACTED: Maiti et al. Ameliorative Properties of Boronic Compounds in In Vitro and In Vivo Models of Alzheimer's Disease. Int. J. Mol. Sci. 2020, 21, 6664.

International journal of molecular sciences, 26(13): pii:ijms26136396.

The journal retracts the article titled "Ameliorative Properties of Boronic Compounds in In Vitro and In Vivo Models of Alzheimer's Disease" [...].

RevDate: 2025-07-12
CmpDate: 2025-07-12

Merighi S, Fernandez M, Nigro M, et al (2025)

PEMFs Restore Mitochondrial and CREB/BDNF Signaling in Oxidatively Stressed PC12 Cells Targeting Neurodegeneration.

International journal of molecular sciences, 26(13): pii:ijms26136495.

Alzheimer's disease (AD), the most prevalent form of neurodegenerative dementia, is characterized by progressive cognitive decline and neuronal loss. Despite advances in pharmacological treatments, current therapies remain limited in efficacy and often induce adverse effects. Increasing evidence highlights oxidative stress, mitochondrial dysfunction, and disrupted neurotrophic signaling as key contributors to AD pathogenesis. Pulsed electromagnetic fields (PEMFs) are emerging as a non-invasive, multifactorial approach with promising biological effects. In this study, we investigated the neuroprotective potential of PEMFs in NGF-differentiated PC12 cells exposed to hydrogen peroxide (H2O2) or amyloid-β peptide (Aβ), both of which model pathological features of AD. PEMF treatment significantly counteracted H2O2- and Aβ-induced cytotoxicity by restoring cell viability, reducing reactive oxygen species production, and improving catalase activity. Furthermore, PEMFs preserved the mitochondrial membrane potential and decreased caspase-3 activation and chromatin condensation. Mechanistically, PEMFs inhibited ERK phosphorylation and enhanced cAMP levels, CREB phosphorylation, and BDNF expression, pathways known to support neuronal survival and plasticity. In conclusion, these findings suggest that PEMFs modulate multiple stress response systems, promoting neuroprotection under oxidative and amyloidogenic conditions.

RevDate: 2025-07-12
CmpDate: 2025-07-12

Kaluza M, Ksiazek-Winiarek D, Szpakowski P, et al (2025)

Polyphenols in the Central Nervous System: Cellular Effects and Liposomal Delivery Approaches.

International journal of molecular sciences, 26(13): pii:ijms26136477.

Neurodegenerative and neuroinflammatory diseases of the central nervous system are closely linked to aging and sustained oxidative and inflammatory stress. Polyphenols, plant-derived secondary metabolites, exhibit broad biological activities, including antioxidant and anti-inflammatory effects, the modulation of pathways such as PI3K/Akt, MAPK, Nrf2, and CREB, and the regulation of neurogenesis and microglial activation. This review focuses on the cell-specific actions of selected polyphenols in neurons, astrocytes, microglia, and oligodendrocytes within the context of Alzheimer's disease, Parkinson's disease, and multiple sclerosis. A major limitation to the therapeutic use of polyphenols is their poor bioavailability, due to instability, low solubility, and limited blood-brain barrier penetration. Liposomal nanocarriers are explored as promising delivery systems to overcome these barriers. Both conventional and functionalized liposomes (e.g., PEGylated, receptor-targeted) are discussed, alongside in vitro and in vivo studies demonstrating enhanced efficacy compared to free compounds. Intranasal delivery is also presented as a viable alternative to oral administration. Overall, polyphenols offer great potential as neuroprotective agents, and liposome-based delivery platforms have the potential to significantly enhance their clinical potential, provided that key formulation and targeting issues are addressed.

RevDate: 2025-07-12
CmpDate: 2025-07-12

Sharma N, SSA An (2025)

Soil to Synapse: Molecular Insights into the Neurotoxicity of Common Gardening Chemicals in Alzheimer's and Parkinson's Disease.

International journal of molecular sciences, 26(13): pii:ijms26136468.

The common gardening herbicides and fertilizers are crucial for weed control and plant growth, yet they may have potentially harmful impacts on neurological health. This review explored the possible effects of these chemicals on neurodegenerative disorders, especially Alzheimer's disease (AD) and Parkinson's disease (PD). The mode of action of several frequently used gardening chemicals (paraquat, glyphosate, 2,4-dichlorophenoxyacetic acid: 2,4-D, and ammonium chloride) in AD and PD has been highlighted. The mechanisms involved are glutamate excitotoxicity, dopaminergic pathway disruption, oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic dysfunction, and gut-brain-axis dysregulation, crucial in the pathophysiology of AD and PD. Although the links between these substances and neurodegenerative conditions remained to be seen, growing evidence indicated their detrimental effects on brain health. This highlights the need for further research to understand their long-term consequences and develop effective interventions to mitigate the adverse effects of commonly used chemicals on human health and the environment.

LOAD NEXT 100 CITATIONS

RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

963 Red Tail Lane
Bellingham, WA 98226

206-300-3443

E-mail: RJR8222@gmail.com

Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

RJR Picks from Around the Web (updated 11 MAY 2018 )