👤 Wei-Ling Chang

Cholinergic dysfunction is a key contributor to cognitive impairment observed in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Although acetylcholinesterase (AChE) inhibitors have been the mainstay of symptomatic treatment for over two decades, their limited efficacy and adverse effects underscore the need for alternative therapeutic approaches. Recent evidence indicates that mechanical stimulation can modulate neuronal and glial signaling through mechanotransduction, suggesting a potential strategy to enhance cognitive function via non-pharmacological means. Here, we developed a head-mounted vibrotactile stimulation system (HVSS) that delivers controlled vibration to the cranium and evaluated its effects in a pharmacological model of acute cholinergic dysfunction induced by scopolamine. To this end, male C57BL/6 mice received scopolamine (1 mg/kg, i.p.; on days 7, 14, and 28) and were exposed to daily vibrotactile stimulation at 20, 40, or 80 Hz for 28 days. Behavioral performance was assessed using passive avoidance and Morris water maze tests, followed by biochemical and histological analyses. HVSS at 40 Hz and 80 Hz significantly improved cognitive performance, enhanced hippocampal cholinergic function, reduced oxidative damage, and upregulated memory-related signaling genes, including BDNF, PI3K, AKt, ERK1/2, CREB, and CAMK4. These findings suggest that high-frequency HVSS improves memory hippocampal cholinergic function via activation of memory-related signaling pathways, highlighting its potential as a safe, non-pharmacological neuromodulatory strategy for cholinergic dysfunction-related cognitive decline. Show less

Obesity and Alzheimer’s disease (AD) are epidemiologically associated. The locus coeruleus (LC)—the brain’s primary and most significant source of norepinephrine—is one of the earliest sites of neurodegeneration in AD. The LC participates in feeding behavior through connections with the hypothalamus. The cellular composition of the LC has been characterized at single-cell resolution. However, the constituent cellular signatures of genes related to energy homeostasis—such as the melanocortin pathway genes—in the LC are unclear. We performed single-nucleus RNA sequencing and spatial transcriptomics (Visium) in the human LC, and HiPlex RNAscope in the LC of mice. The melanocortin pathway gene The online version contains supplementary material available at 10.1186/s40478-026-02287-x. Show less

Anorexia nervosa (AN) is a complex psychiatric disorder with both psychiatric and metabolic underpinnings. This study aims to explore the genetic architecture of AN and the interplay between its psychiatric and metabolic components. Through a meta-analysis of AN GWAS data from European and Finnish populations, we identified a novel genome-wide significant locus near the SOX5 gene. Genetic correlation and Mendelian randomization analyses revealed shared and potentially causal relationships between AN and multiple psychiatric and metabolic traits. Local genetic correlation analysis identified 185 significant genomic regions contributing to shared heritability between AN and correlated phenotypes, with 100 loci demonstrating pleiotropic effects across multiple traits. The MTAG analyses identified 86 significant loci (34 overlapping with local genetic correlation results), including 25 novel loci such as brain-relevant VAMP2 (17p13.1) and metabolic-neurological hubs LPL (8p21.3) and BDNF (11p14.1). Gene Co-expression Network Analysis (WGCNA) further identified key gene modules associated with both metabolic and neurological pathways, particularly highlighting synaptic signaling and lipid metabolism. Single-cell transcriptomic analysis further resolved this genetic risk to the cellular level, confirming its concentration in limbic and striatal GABAergic neurons and extending the implicated circuitry to include cortical regions involved in motor function. These findings collectively demonstrate the intricate genetic interplay between psychiatric and metabolic pathways in AN, underscoring the necessity of an integrated approach to understanding its pathogenesis. Show less

This study aimed to investigate whether aerobic exercise (AE) and AE combined with whole-body vibration (AE+WBV) exert distinct effects on neurocognitive outcomes and circulating myokines, and to further explore the potential molecular mechanisms underlying exercise-induced neurocognitive changes. A total of 72 postmenopausal women were randomly assigned to an AE, AE+WBV, or control group. At baseline and after the 16-week intervention or control period, both behavioral and event-related potential (ERP) indices were assessed during a visuospatial working memory (WM) task, and serum myokine concentrations of brain-derived neurotrophic factor (BDNF), irisin, insulin-like growth factor-1 (IGF-1), osteocalcin (OC), interleukin-6 (IL-6), and IL-15 were measured. Reaction times, ERP P2 amplitudes, and P2 and P3 latencies remained unchanged postintervention. However, AE significantly improved accuracy rates (ARs) under the two-item WM condition and increased P3 amplitudes under both the two- and four-item conditions. AE+WBV produced broader improvements in both ARs and P3 amplitudes under the two- and four-item conditions. Regarding molecular outcomes, neither intervention affected IL-6 concentrations. In the AE group, BDNF and irisin levels increased significantly postintervention, whereas IL-15 levels decreased. In the AE+WBV group, IGF-1, irisin, and OC levels increased postintervention and IL-15 levels decreased. Changes in neurocognitive performance were significantly associated with BDNF and OC in the AE group, and changes in neurophysiological performance were significantly associated with IGF-1 and irisin in the AE+WBV group. Collectively, these findings suggest that AE and AE+WBV promote distinct myokine profiles and partially improve neurocognitive performance in postmenopausal women, with AE+WBV demonstrating stronger effects, likely mediated by different molecular pathways. Show less

Valproic acid (VPA) is recognized for its neurotrophic properties and is widely used in psychiatric and peripheral disorders, while dextromethorphan (DM) has demonstrated anti-inflammatory and neuroprotective effects. This study examined whether adjunctive DM provides additional benefits on cognitive or immunomodulatory beyond standard VPA treatment in bipolar disorder (BD). BD aged 20-65 received open-label VPA (500-2500 mg/day; target blood level 50-100 μg/dl) for one week and were then randomized to VPA plus placebo (BDVPA) or VPA plus extended-release DM (BDVPA + DM; 30 or 60 mg/day) for twelve weeks. Neuropsychological measures (Continuous Performance Test, CPT; Wechsler Memory Scale-Revised, WMS-R), symptom severity, cytokines, and BDNF were assessed at baseline and post-treatment. A total of 109 participants (mean age 31.04 years, SD = 10.04) were enrolled; 96 completed cognitive testing and blood sampling (66 BD Show less

Brain-derived neurotrophic factor (BDNF) crosses the blood-brain barrier and may serve as a marker of neuroplasticity. This study evaluated whether serum levels of mature BDNF, proBDNF, and matrix metalloproteinase-9 (MMP-9) can predict functional recovery after stroke. In this prospective observational study, 93 patients with unilateral stroke and motor impairment were recruited. Clinical, and demographic data, as well as serum levels of mature BDNF, proBDNF, and MMP-9 were collected. Functional assessments measuring stroke severity, cognition, motor function, balance, and mood were conducted at three timepoints: after acute care (T0), 2 weeks post-rehabilitation (T1), and 3 months post-onset (T2). Mature BDNF significantly decreased from T0 to T2 (p = 0.003), while proBDNF remained stable. MMP-9 declined consistently across timepoints (p < 0.001). MMP-9 levels at baseline differed by BDNF genotype (p < 0.05). However, none of the biomarkers independently predicted functional recovery. Functional outcomes improved significantly over time (p < 0.001), with baseline functional scores being the strongest predictors at T1 and T2. Although these biomarkers were not independent predictors of recovery, their longitudinal trajectories may reflect underlying neurobiological recovery mechanisms during rehabilitation, although their prognostic utility remains inconclusive. Show less

Chemotherapy-induced peripheral neuropathy (CIPN) remains a major unmet challenge in oncology, affecting treatment adherence and patient quality of life. Despite its prevalence, reliable predictive biomarkers and targeted neuroprotective strategies remain elusive. This study integrates clinical data, whole-genome sequencing, and translational research to identify genetic determinants of CIPN susceptibility and validate therapeutic approaches. Through comprehensive analysis of patients with colorectal cancer, including neurophysiological evaluations and CIPN-specific quality-of-life assessments, we identified the Show less

The purpose of this study was to analyze and compare cytokine and growth factor levels in modified autologous conditioned serum (mACS) and autologous serum (AS) and to evaluate their therapeutic effects in a benzalkonium chloride (BAK)-induced murine dry eye model. Serum samples were obtained from twenty healthy volunteers and analyzed by ELISA. A dry eye model was established in twenty-four C57BL/6 mice by topical application of 0.2% BAK twice daily for seven days. The mice were evenly divided into three subgroups: saline-treated, 0.5% AS-treated, and 0.5% mACS-treated. The right eyes were treated, and the left eyes served as untreated controls. Eyeballs were harvested on days 7 and 14 for immunofluorescence staining. Results showed that neuroprotective factors (BDNF and fractalkine), pro-inflammatory cytokines (IL-1β, IL-6, MIF, TNF-α), and VEGF-A were significantly elevated in the mACS group, whereas PDGF-BB was significantly reduced. Furthermore, immunofluorescence analysis demonstrated a significantly greater recovery of central corneal nerve fibers in the mACS-treated group compared with the saline group at day 7 (p < 0.01). At day 14, the mACS-treated group continued to show a trend toward increased central corneal nerve regeneration, although this difference did not reach conventional statistical significance (p < 0.1). No significant differences were observed between the AS- and saline-treated groups. In conclusion, compared with AS, mACS demonstrates a cytokine profile suggestive of enhanced neuroprotective potential and may facilitate corneal nerve regeneration in the BAK-induced murine dry eye model. Show less

PINK1-dependent activation of PRKN/parkin on depolarized mitochondria causes mitophagy. The deficiency of NME3, a nucleoside diphosphate kinase/NDPK on the outer mitochondria membrane (OMM), is associated with a fatal neurodegenerative disorder. Here, we report that NME3 deficiency impairs p-S65-ubiquitin (Ub)-dependent PRKN binding on depolarized mitochondria without involving the loss of Ub phosphorylation by PINK1. Our mechanistic investigation revealed that NME3 interacts with PLD6/MitoPLD to generate phosphatidic acid (PA) from cardiolipin on the OMM of damaged mitochondria after depolarization. This lipid signal is essential for positioning MFN2 nearby PINK1 for phosphorylation of Ub conjugates on MFN2, thus enabling the subsequent amplification of PRKN binding to mitochondria. We provide further evidence that mitochondria-endoplasmic reticulum (Mito-ER) tethering prohibits the proximity of MFN2 with PINK1 and PRKN amplification on mitochondria. Importantly, the loss of NME3-regulated PA signal causes Mito-ER tethering. Overall, our findings suggest that NME3 cooperates with PLD6 to generate PA as a critical step in Mito-ER untethering, allowing MFN2 access to PINK1 for p-S65-poly-Ub-dependent feedforward activation of PRKN. Show less

The brain-derived neurotrophic factor (BDNF) plays a crucial role in neuroprotection, and we have previously demonstrated BDNF-mediated neuroprotective effects in mesenchymal stromal cells (MSCs). The present study aimed to investigate whether BDNF-overexpressing MSCs enhance the therapeutic efficacy of naïve MSCs in a preclinical model of severe neonatal intraventricular hemorrhage (IVH). We exposed primary rat neuronal cells to 40 U of thrombin overnight Show less

Diabetic refractory wounds are a severe complication of diabetes, often synchronized with diabetic peripheral neuropathy. In this study, we demonstrated a significantly downregulated expression of calcitonin gene-related peptide (CGRP) in the skin tissues of both diabetic patients and diabetic mouse models. This observation implies the crucial role of CGRP in diabetic wound healing. Based on this discovery, we engineered glucose-responsive along with sustained-release antibacterial hydrogel microspheres (BA-HPCS@CGRP) for the controlled delivery of CGRP and conducted systematic evaluation of its therapeutic efficacy. In vitro findings demonstrated that microspheres not only directly enhanced the migration and tube formation capabilities of endothelial cells impaired by high glucose but also further facilitated the restoration of endothelial cell function by promoting the secretion of angiopoietin-like protein 4 (Angptl4) by macrophages after switching to M2 phenotype by CGRP. The results from diabetic mouse models showed that BA-HPCS@CGRP accelerated diabetic wound healing by modulating macrophage polarization towards to M2 phenotype and reduced inflammation, promoted neurovascular regeneration and restored the local CGRP expression. These findings suggest that sustained releasing of low concentration of CGRP provides novel therapeutic approaches for diabetic wounds via modulating macrophage. Moreover, BA-HPCS@CGRP achieves comprehensive sequential therapy through the synergistic modulation of the "neuro-immune-vascular" axis, which might open new perspective to chronic wounds and regenerative medicine. Show less

Ischemic stroke is a heterogeneous disease influenced by inflammation, coagulation dysfunction, and metabolic disturbances. However, integrated analysis incorporating these biological domains for patient stratification remain limited. A retrospective study of 132 ischemic stroke patients was conducted. Clinical, coagulation, inflammatory, and metabolic parameters were collected. Principal component analysis (PCA) was applied for dimensionality reduction and visualization. PCA revealed underlying heterogeneity among patients. Validated Data driven clustering identified biologically distinct ischemic stroke subtypes based on inflammation, coagulation, and metabolic profiles. This stratification highlights the heterogeneity of ischemic stroke and may inform future personalized approaches to risk assessment and management. Show less

The comparative roles of triglyceride-rich lipoproteins (TRLs) and low-density lipoproteins (LDLs) in abdominal aortic aneurysm (AAA) pathogenesis are unclear. To evaluate the putative causal role of TRLs in AAA, quantify the relative effect on AAA risk ("aneurysmogenicity") of TRL vs LDL particles, and prioritize lipid-lowering drug targets for AAA prevention and treatment. We performed summary-level and individual-level Mendelian randomization (MR) analyses. Genetic variants were selected from 383,983 UK Biobank participants and ranked into 10 sets of variants where set 1 predominantly affected LDL cholesterol (LDL-C) and set 10 predominantly affected TRL cholesterol (TRL-C; and with mixed effects for intermediate variant sets). AAA outcome data were obtained from AAAgen (37,214 cases), FinnGen (4,439 cases), and the VA Million Veteran Program (MVP; 23,848 cases). Multivariable MR was used to assess the independent roles of LDL-C and TRL-C in AAA. For each set of variants, MR or logistic regression was used to estimate AAA odds ratios (ORs) per 10 mg/dL higher apolipoprotein B (apoB). Interaction analyses were conducted between a statin-like LDL-C-lowering variant set (set 3) and a TRL-C-lowering variant set (set 10). Drug-target MR was performed to evaluate lipid-lowering targets relevant to LDL-C- and TRL-C-lowering. Genetically predicted LDL-C and TRL-C concentrations were each associated independently with genetic liability for AAA after mutual adjustment, with 3.0 to 5.5 times stronger associations for TRL-C compared to LDL-C on a per-cholesterol basis. In AAAgen, the AAA OR per 10 mg/dL increased apoB concentrations were 1.10 (95% CI, 1.05-1.14) for variant set 1 (LDL-C-predominant) and 1.89 (95% CI, 1.69-2.11) for variant set 10 (TRL-C-predominant). Using the ratio of log(OR) per 10 mg/dL apoB for set 10 versus set 1 as a conservative estimate of relative aneurysmogenicity, TRLs were approximately 3.2 to 6.9 times more aneurysmogenic than LDLs across the three studies. No evidence of interaction was observed between LDLs and TRLs, indicating additive contribution to AAA risk. Drug-target MR supported strong protective associations for genetically proxied inhibition of TRL-pathway targets, particularly TRLs are at least threefold more aneurysmogenic than LDLs on a per-particle basis. Therapeutic strategies targeting TRL-C -especially via Show less

BACKGROUNDMetabolic dysfunction-associated steatotic liver disease (MASLD) has a substantial inherited component. Rare variants in apolipoprotein B gene (APOB) have been implicated in susceptibility to liver steatosis, but their role in disease progression and outcomes is unclear.METHODSWe investigated APOB rare variants in a case-control cohort of people with advanced MASLD versus healthy controls (n = 510 and 261, respectively), a family-based study (n = 43 and literature meta-analysis), the Million Veteran Program (MVP) cohort (n = 94,885), and the UK Biobank (UKBB) (n = 417,657).RESULTSIn the clinical cohort, APOB variants were enriched in people with advanced MASLD (OR 13.8, 95% CI: 2.7-70.7, P = 0.002) and associated with lower circulating lipids, but higher MASLD activity and fibrosis (P < 0.05). In the family study, APOB variants segregated with hepatic steatosis and fibrosis (P < 0.05). Cross-ancestry meta-analysis of the study cohorts yielded pooled ORs for cirrhosis and hepatocellular carcinoma (HCC) of 1.82, 95% CI: 1.33-2.49 and 3.53, 95% CI: 2.09-5.98, respectively. Variants affecting specifically ApoB100 had a 3-fold greater effect on hepatic lipid metabolism compared with those impairing also ApoB48 and were specifically protective against coronary artery disease (P < 0.05). The variants affected cirrhosis risk similarly, but ApoB48/100 had a larger effect on HCC (P < 0.05).CONCLUSIONSRare APOB variants predispose individuals to advanced MASLD and HCC, with distinct contributions from disrupted VLDL and chylomicrons secretion. These findings highlight the interplay between hepatic and intestinal lipid handling, suggesting that APOB genotyping may enhance MASLD risk stratification and patient identification.FUNDINGEuropean Union, Italian Ministry of Health, Swedish Research Council, Veterans Health Administration, NIH. Show less

Vitiligo pathogenesis involves progressive melanocyte loss and keratinocyte dysfunction, which are driven primarily by oxidative stress resulting from excessive ROS accumulation. We engineered a temporally controlled hydrogel microneedle system that integrates ginseng-derived exosomes (G-Exos) with biomimetic polydopamine nanoparticles (PDA@PEGs) to concurrently target the pathogenic triad of vitiligo, including oxidative stress, inflammation, and melanocyte deficiency. This system employs methacrylated hyaluronic acid (HAMA) hydrogel microneedles for rapid PDA@PEG release while utilizing glyceryl monostearate micelles to achieve matrix metalloproteinase-9 (MMP-9)-responsive G-Exo release at inflammatory foci, enabling intelligent spatiotemporal control. Functionally, G-Exos help restore redox homeostasis and suppress inflammation through bioactive constituents, thereby protecting melanocytes and enhancing keratinocyte proliferation. Moreover, PDA@PEG promotes repigmentation through the dual mechanisms of exogenous melanin deposition and endogenous melanogenesis stimulation. In murine models, this strategy achieves significant repigmentation within 3 weeks by activating follicular stem cells, upregulating melanogenic markers (Tyr/Mc1r), increasing antioxidant defense (ApoE), and suppressing inflammatory signaling (IL-17). This natural-biomimetic hybrid design leverages biocompatible materials to co-target multiple pathological axes, offering a novel self-adaptive approach for microenvironmental rehabilitation in vitiligo. Show less

This study investigated longitudinal plasma serotonin dynamics across the Alzheimer's disease (AD) continuum (cognitively normal [CN], mild cognitive impairment [MCI], and AD) to determine whether baseline serotonin and its 24-month change are associated with CSF amyloid-β (Aβ42), tau biomarkers, amyloid PET burden, structural brain integrity, and cognitive decline. Data from 959 ADNI participants (CN = 306, MCI = 421, AD = 232) with baseline and 24-month follow-up were analyzed. Measures included plasma serotonin, CSF biomarkers (Aβ42, total tau, p-tau181), florbetapir PET, MRI (hippocampal volume, cortical thickness), and cognitive tests (MMSE, ADAS-Cog 11, CDR-SB). Group differences were tested using ANOVA or Kruskal-Wallis, and associations were examined via partial correlations and mixed-effects models adjusted for age, sex, education, and APOE ε4, with FDR correction. The results revealed that baseline plasma serotonin levels showed a stepwise decline across the clinical continuum (CN > MCI > AD; p ≤ 0.05), consistent with progressive serotonergic dysregulation. In AD participants, higher baseline serotonin was significantly associated with less amyloid pathology and preserved brain structure, including higher CSF Aβ42 (β = 0.28, FDR p = 0.01), lower florbetapir PET SUVR (β = -0.31, FDR p = 0.02), and larger hippocampal volume (β = 0.33, FDR p = 0.02). Higher serotonin was also linked to better cognitive performance (MMSE: β = 0.22, FDR p = 0.02; ADAS-Cog 11: β = -0.24, FDR p = 0.02). Longitudinally, decreases in serotonin over 24 months in AD were associated with worsening amyloid burden (ΔPET SUVR: β = -0.29, FDR p = 0.02) and accelerated hippocampal atrophy (β = 0.32, FDR p = 0.01). Baseline serotonin predicted smaller 24-month declines in CSF Aβ42 (β = 0.28, FDR p = 0.01) and reduced hippocampal volume loss (β = 0.31, FDR p = 0.01). In CN and MCI groups, associations between serotonin and AD biomarkers or cognitive outcomes were not significant after FDR correction. On the whole, lower plasma serotonin levels are linked to amyloid pathology, hippocampal neurodegeneration, and cognitive decline in AD, supporting serotonin's potential as a stage-specific biomarker and mechanistic contributor to disease progression. Integrative longitudinal studies are needed to clarify causality and evaluate serotonergic pathways as therapeutic targets. Show less

This review overviewed the recent paradigm shifts in the diagnosis and management of Alzheimer's disease (AD), emphasizing the 2024 Alzheimer's Association (AA) revised criteria, advances in cerebrospinal fluid (CSF) and blood-based biomarkers (BBMs), and practical considerations for anti-amyloid monoclonal antibody therapy. We conducted a narrative appraisal of consensus frameworks (2018 National Institute on Aging-Alzheimer's Association [NIA-AA] amyloid, tau, and neurodegeneration [AT(N)] and the 2024 AA criteria), clinical practice guidance from AA released in 2025, regulatory status of CSF and BBMs. Intended-use settings (triage vs. confirmatory) of BBMs and implementation of anti-amyloid anti-body treatments (lecanemab or donanemab) in real-world practice in Korea were also reviewed. The 2024 AA criteria define AD biologically and designate A and T as core biomarkers; Core 1 biomarkers can establish AD irrespective of symptoms, whereas Core 2 biomarkers refine staging. A two-cutoff BBM strategy (positive/intermediate/negative) reduces misclassification and guides confirmatory CSF/positron emission tomography (PET) or retesting. BBMs now approach CSF/PET accuracy for amyloid detection, enable triage and, in selected settings, confirmation, and show utility for monitoring treatment response. Integration of clinical stages (1-6) with biological stages (A-D) clarifies syndrome-pathology discordance. Special scenarios-maintenance after induction, APOE ε4 homozygotes, Down syndrome, and serious mental illness-require individualized risk-benefit assessment. In South Korea, constrained access to tau PET and some BBMs necessitates Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision-anchored evaluation with selective biomarker testing. Biomarker-oriented diagnosis and anti-amyloid therapies are reshaping AD care. Priorities include rigorous validation of BBMs across populations, equitable access to core biomarkers, safety strategies, and real-world evidence to implement maintenance and special-population care pathways. Show less

Atherosclerosis currently lacks effective therapeutic strategies specifically targeting and inhibiting foam cell formation. In this study, we engineered a macrophage nanoparticle composite drug delivery system that utilizes macrophages for competitive lipid uptake, coupled with ROS-responsive statin nanoparticles aimed at inhibiting cholesterol synthesis. This integrated system embodies a "smart immunomodulatory" approach, leveraging the inherent activity and targeted capabilities of immune cells. Experimental results demonstrated that this system significantly reduced lipid accumulation within foam cells by inhibiting cholesterol uptake, promoting cholesterol efflux and inhibition of apoptosis. These effects were mediated through microenvironmental optimization and upregulation of ABCA-1 and SR-BI expression. In an APOE knockout mouse model of atherosclerosis, the system effectively lowered lipid levels, modulated inflammatory responses, and significantly reduced foam cell formation and atherosclerotic plaque development. The system enhanced Treg cell proliferation and TGF-β secretion. Moreover, the system demonstrated high biocompatibility and therapeutic efficacy, training macrophages to revert to a low-lipid and M2 phenotype. This targeted drug delivery system integrates multiple therapeutic mechanisms, including inhibition of cholesterol uptake, enhancement of cholesterol efflux, and immunomodulation, providing a promising new strategy for the treatment of atherosclerosis. Show less

Monocyte adhesion to vascular endothelial cells is a critical step in the pathogenesis of atherosclerosis. While unconventional myosins are known to participate in various cellular activities, their specific role in monocyte-endothelium adhesion remains unclear.In the present study, we investigated the effects of Myosin IF (Myo1f), a class I unconventional myosin, on atherosclerosis and its underlying mechanisms. A high-cholesterol diet was administered to apolipoprotein E-KO (Apoe Myo1f expression was found to be significantly increased in PBMCs of patients with coronary artery disease. Moreover, Myo1f-deficient mice exhibited a notable reduction in atherosclerotic plaque area and lipid deposition compared to Apoe Our data indicate that Myo1f regulates monocyte adhesion and contributes to the pathogenesis of atherosclerosis by recruiting EPLINα, which stabilizes F-actin. This stabilization enhances MRTFA nuclear translocation, thereby promoting ITGB2 transcription. Show less

Decreasing body mass index (BMI) from midlife to late life has been linked to increased Alzheimer's disease (AD) risk and cognitive decline; however, the association with in vivo AD pathology remains unclear. This study aimed to clarify the relationship between midlife-to-late-life BMI changes and in vivo AD pathologies, specifically amyloid-β (Aβ), tau, and AD-signature region cerebral glucose metabolism (AD-CM). This observational cohort study included non-demented older adults recruited from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) between January 2014 and December 2020. Participants underwent clinical evaluations and positron emission tomography (PET) imaging to measure brain Aβ, tau, and AD-CM. Midlife BMI was retrospectively estimated from self-reported weight at ages 40–50 years, while late-life BMI was measured during the study. Participants were categorized based on BMI changes as decreasing (≤ − 4%), stable (− 4% to < 4%), or increasing (≥ 4%). Associations between BMI patterns and AD pathologies were analyzed using multiple linear regression models. A total of 268 participants (mean age 66.6 ± 7.9 years; 56.3% women; 22.5% APOE ε4 carriers) were analyzed. Higher midlife BMI correlated significantly with lower AD-CM (β = − 0.009; 95% CI, − 0.015 to − 0.003; A decreasing BMI trajectory from midlife to late life is associated with enhanced AD-related neurodegeneration, underscoring the clinical importance of monitoring long-term body weight changes in relation to Alzheimer's disease pathophysiology. The online version contains supplementary material available at 10.1186/s13195-026-01967-z. Show less

BackgroundSedentary behavior is common in older adulthood and is associated with poor health outcomes. Less is known about how sedentary behavior relates to cognition in older adulthood and how it relates to increased risk for cognitive decline associated with Alzheimer's disease (AD).ObjectiveWe sought to examine these associations in a large, population-based cohort of community-dwelling older adults residing in a Rust Belt region of the United States.MethodsA subset of the population-based Monongahela-Youghiogheny Healthy Aging Team (MYHAT) participants (n = 193) completed 7 days of wrist-accelerometry following comprehensive neuropsychological assessment. Cross-sectional linear regression models related sedentary time to domains of cognition. Models were adjusted by age, sex, education, and Show less

Microglia monitor disease stimulation, neuronal apoptosis, and neural repair, and their overactivation-induced inflammation plays a key role in the pathogenesis of Alzheimer's disease (AD). Morroniside (Mor), an iridoid glycoside compound in Cornus officinalis, is one of the effective active components. The effects of Mor on antioxidant stress, antiapoptosis, and nerve repair function have been widely studied, but the mechanism of Mor in AD treatment remains unclear. To study the neuroprotective effects of Mor and elucidate the molecular mechanisms underlying its improvement of AD symptoms, we used ApoE4 transgenic mice and ApoE4-transfected BV2 cells as models of AD, focusing on microglia phenotype, function, and neuroinflammation. The 10-month-old mice were randomly divided into the ApoE3 control group (ApoE3 + Veh), the ApoE4 model group (ApoE4 + Veh), and the ApoE4 + Mor 10, 20, and 40 mg/kg groups as in vivo models. The in vitro BV2-ApoE model was constructed via lentiviral transfection. The effects of Mor on cognitive function of AD models were assessed through behavioral tests, western blot, immunofluorescence staining, and ELISA to measure changes of related pathological and inflammatory factors. Mor improved the cognitive function of ApoE4 transgenic mice by reducing Aβ plaques in the brain, improving the structural lesions of hippocampal neurons, and increasing synaptic plasticity in the brain of AD mice. In addition, Mor promoted the transformation of microglia from the M1 to the M2 phenotype, inhibited the activation of the CX3CR1/PU.1 signaling axis, and alleviated the dysfunction of microglia both in vitro and in vivo. CX3CR1 siRNA and PU.1 siRNA were used further to verify the regulatory effect of Mor on microglia phenotype. Our findings indicate that Mor can inhibit neuroinflammation, reduce Aβ accumulation, and improve synaptic damage in ApoE4 mice via the CX3CL1/CX3CR1/PU.1 pathway regulating the phenotype and function of microglia. This study provides a new therapeutic candidate for the prevention and treatment of AD. Show less

Air pollution exposure is associated with increased cardiovascular morbidity and mortality worldwide. Previous studies provide a causal relationship between exposure to particulate matter (PM) and atherosclerosis development. We have previously demonstrated increased aortic atherosclerosis and adverse metabolic effects in hyperlipidemic mice exposed to ambient ultrafine PM. However, the underlying mechanisms by which ambient PM promotes systemic effects leading to worsened atherosclerosis remain unknown. We have recently shown that the gut microbiota composition was altered in mice exposed to re-aerosolized PM in the ultrafine-size range for 10 weeks. We hypothesized that sub-chronic exposure to ultrafine PM induces gut dysbiosis in association with systemic prooxidative effects and atherosclerotic lesion development. Male apolipoprotein E knockout (ApoE Show less

Working memory training (WMT) has been shown to improve WM in healthy older adults, patients with mild cognitive impairment, and individuals with HIV, including improvements in WM network efficiency. This randomized study explored near-transfer and far-transfer effects of WMT and examined whether Participants were recruited from local communities. After screening and baseline evaluation, participants were randomized to either 25 sessions of adaptive or nonadaptive WMT (as an active control) over 5-8 weeks. Nontrained near-transfer WM tests, far-transfer tests, and self-reported executive functioning were performed at baseline, 1-month, and 6-month follow-ups. Genotyping included A total of 107 participants (60 with HIV, 47 SN) completed adaptive WMT, and 70 active controls (36 with HIV, 34 SN) completed nonadaptive WMT. Overall, 96 adaptive WMT participants and 68 active controls completed the 1-month follow-up while 77 adaptive WMT participants and 37 active controls completed the 6-month follow-up. Adaptive WMT led to higher improvement indices in SN participants than in the HIV group (training*HIV serostatus: Adaptive WMT improved near-transfer WM, far-transfer performance, and self-reported executive functioning in all participants, but more sustained effects among participants with HIV. These findings suggest that adaptive WMT can be an effective adjunctive therapy for cognitive deficits in PWH, especially in those with This study provides Class IV evidence that adaptive WMT improves near-transfer WM, far-transfer performance, and self-reported executive functioning in patients with or without HIV, regardless of Show less

Apolipoprotein E (ApoE) mediates the bidirectional transport of lipids between cells. In the brain, this includes the transfer of lipids from neurons to glia. ApoE4, a major risk factor for Alzheimer's disease, impairs this transport pathway, increasing risk for neurodegeneration. ApoE2 and ApoE3 Christchurch (ApoE3Ch) confer resistance to disease, yet little is known regarding how these variants affect lipid trafficking. Here, we explored how lipoprotein particles containing different ApoE isoforms affect neuronal health. We demonstrate that ApoE2 and ApoE3Ch particles protect neurons from ferroptosis by extracting oxidized unsaturated lipids through the ABCA7 transporter. ApoE4 particles, on the other hand, exacerbate the effects of these toxic lipids, leading to endolysosomal dysfunction. By reducing the oxidized lipid burden in ApoE4 neurons, ApoE2 and ApoE3Ch particles rescue endolysosomal function and restore defects in neuronal activity caused by excitotoxicity. Our findings reveal how ApoE2 and ApoE3Ch help protect neurons from neurodegeneration. Show less

Bovine tuberculosis (bTB) is a chronic infectious disease caused by the Mycobacterium bovis (M. bovis). Rapid, cost-effective, and accurate diagnosis of bTB remains a significant clinical challenge globally. In this study, we performed a comprehensive proteomic analysis to evaluate the discriminatory power of plasma and plasma exosomes for bTB diagnosis. We compared protein expression profiles across three groups: M. bovis-negative controls (bTB_N, n = 10), M. bovis-positive cases (bTB_P, n = 10), and co-infected animals (Other_P, n = 10) with Brucella, infectious bovine rhinotracheitis virus (IBRV), and bovine viral diarrhea-mucosal disease virus (BVDV). Quantitative analysis identified 3820 exosomal proteins-2.27-fold more than the 1686 plasma proteins detected. Exosomal proteins exhibited superior sample clustering and discriminative capacity for infected groups. Notably, 227 plasma and 861 exosome-derived proteins were uniquely differentially expressed in bTB (bTB-specific DEPs). Pathway enrichment analysis revealed that exosome-specific DEPs were significantly enriched in TB-related pathways, including neutrophil extracellular trap (NET) formation, endocytosis, and tuberculosis, exhibiting greater biological relevance compared to plasma-specific DEPs. Furthermore, eight candidate proteins (APOE, FBLN5, VDAC1, ABCE1, LMAN1, PLG, SPP1, and SRP9) demonstrated high specificity for bTB discrimination, with two (FBLN5 and SPP1) displaying stage-specific expression patterns during M. bovis infection. This study underscore plasma exosome as a highly promising source of biomarkers for bTB diagnosis, offering enhanced sensitivity and deeper mechanistic insights over conventional plasma proteome. Show less