Frontiers in Aging Neuroscience最新文献

Microglia, the resident immune cells of the central nervous system (CNS), play a pivotal role in health and disease maintaining homeostasis and mediating neuroinflammatory responses. Their activation is a dynamic and context-dependent process characterized by diverse phenotypic states defined by transcriptomic, proteomic, and morphological characteristics. While lipopolysaccharide (LPS) is widely used as an inflammatory stimulus in microglial research, its physiological relevance remains debated. Interferon gamma (IFNγ), a key pro-inflammatory cytokine involved in immune priming, more closely mimics CNS inflammatory conditions. In this study, we systematically investigated the temporal activation profiles of human iPSC-derived microglia (hiMG) in response to LPS, IFNγ, and their combination. Transcriptomic analysis at 24 h revealed robust differential gene expression, with over 7,000 genes altered by LPS and more than 8,500 by LPS/IFNγ co-stimulation. These profiles partially overlapped with disease-associated microglia (DAM) signatures, including upregulation of S100A9, CD44, ACSL1, and HIF1A, and downregulation of TREM2, GPNMB, FABP3, LGMN, and LPL. Cytokine expression changes were detectable as early as 1 h post-treatment, predominantly following LPS exposure, and displayed distinct early (≤2 h), mid (4-12 h), and late (24-96 h) temporal patterns. IFNγ alone induced modest transcriptomic and cytokine responses but contributed to sustained inflammatory signatures when combined with LPS. Morphological analysis showed marked LPS- and LPS/IFNγ-induced structural remodeling of hiMG consistent with activation. To assess protein-level dynamics, targeted mass spectrometry quantified secreted ApoE, CD44, FUCA1, Galectin-3, and Osteopontin, all relevant to microglial activation, which were compared to cellular protein expression measured by western blot. Time-dependent increases were most prominent following LPS and LPS/IFNγ treatment, although secreted Osteopontin levels were highest with IFNγ alone, highlighting stimulus-specific effects. Collectively, these data demonstrate that microglial activation is highly time- and stimulus-dependent, with LPS eliciting the strongest responses, and IFNγ modulating these effects. Our findings underscore the importance of temporal resolution in modeling microglial activation and provide insight into the mechanistic underpinnings of microglial activation relevant to neurodegeneration and therapeutic targeting.

Introduction: Aged non-human primates have been reported to develop tau pathology; however, most studies lack evidence of any associated neurological symptoms. To determine whether spontaneous tauopathy in cynomolgus macaques manifests with neurological symptoms, we evaluated a symptomatic aged monkey (Monkey T) alongside an asymptomatic control (Monkey A).

Methods: Two male cynomolgus macaques, aged 33-34 years old at the time of necropsy, were examined. They were evaluated using comprehensive behavioral, pathological, and genetic analyses.

Results: Monkey T exhibited progressive neurological symptoms for approximately two years prior to euthanasia, including tremors, nuchal dystonia, and a flexed posture, whereas Monkey A showed no abnormalities. Monkey T demonstrated persistent tremors (6.9 ± 0.7 Hz) and reduced daily motor activity, with modest improvement following L-DOPA administration. Neuropathological evaluation revealed brainstem atrophy and mild depigmentation of the substantia nigra and locus coeruleus. Extensive phosphorylated tau accumulation was observed throughout the brainstem tegmentum, including neurofibrillary tangles, threads, coiled bodies, and astrocytic inclusions. All tau lesions were positive for 4-repeat tau and negative for 3-repeat tau. MAPT sequencing identified four non-pathogenic 3'UTR variants differing between the two monkeys. Isoform analysis showed balanced 3R/4R tau expression in Monkey A but an approximately 1.3-fold increase in 4R tau in Monkey T.

Discussion: The parkinsonian symptoms observed in Monkey T were more likely attributable to widespread tau pathology in the brainstem rather than overt degeneration of the nigrostriatal dopaminergic system. This case represents a rare instance of spontaneous tauopathy in an aged cynomolgus macaque, a condition that is extremely difficult to reproduce experimentally. These findings highlight the potential value of cynomolgus macaques as a relevant model for studying sporadic tauopathies, including tau seeding mechanisms.

[This retracts the article DOI: 10.3389/fnagi.2022.836634.].

Background: The early and accurate identification of Alzheimer's disease (AD) remains a significant clinical challenge. Integrating novel peripheral blood-based biomarkers with established cerebrospinal fluid (CSF) measures may offer a promising strategy to enhance diagnostic accuracy and risk stratification.

Methods: This study enrolled 91 participants who underwent CSF and serum testing. The cohort was randomly divided into a training set (n = 63) and an internal testing set (n = 28). External validation was performed using matched data (n = 30) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (total n = 639). Data collected included demographics, Mini-Mental State Examination (MMSE) total scores, the Functional Activities Questionnaire (FAQ) total scores, CSF phosphorylated tau (pTau181) and amyloid-β (Aβ42) levels, and serum indices such as the albumin-to-globulin (A/G) ratio and platelet-to-lymphocyte ratio (PLR). Predictor selection was performed via univariate and multivariate logistic regression, and a nomogram was developed from the final model. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), calibration curves with mean absolute error (MAE), and decision curve analysis (DCA).

Results: The final predictive model incorporated CSF pTau181, A/G ratio, and PLR (using a cut-off ≥113.22). It demonstrated robust discrimination, achieving an AUC of 0.92 in the training set, 0.86 in the testing set, and 0.83 upon external validation. Calibration was excellent (MAE = 0.039). In the testing set, sensitivity was 0.83 and specificity was 0.86. A higher A/G ratio was associated with a reduced risk of AD progression, whereas a higher PLR was associated with an increased risk.

Conclusion: The combined CSF-peripheral blood biomarker model demonstrates robust discrimination and calibration for predicting AD progression. By linking central tau pathology with peripheral nutritional and inflammatory status, it may aid clinical risk stratification and guide management strategies focused on nutrition and inflammation. Further large-scale, prospective validation is warranted.

Introduction: Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide, characterized by progressive cognitive decline and, in advanced stages, marked motor impairments. These motor deficits are associated with muscle atrophy, mitochondrial dysfunction, and amyloid-β (Aβ) pathology affecting both motor brain areas and peripheral tissues, ultimately contributing to disability, fall risk, and reduced quality of life. Although physical exercise has been shown to confer cognitive and functional benefits in AD, to date, no studies have directly examined the relationship between motor performance and the underlying pathological mechanisms. This study introduces a novel approach by simultaneously addressing muscle pathology and mitochondrial alterations associated with motor decline.

Methods: Twelve-month-old male triple-transgenic (3xTg-AD) and non-transgenic (Non-Tg) mice were assigned to sedentary or exercise groups (n = 16 each group). The exercise protocol combined voluntary wheel running and forced treadmill training, 5 days/week for 4 months. Motor performance was evaluated using open-field, gait analysis, grip strength, and beam walking tests. Post-intervention, histological analyses evaluated Aβ deposition and mitochondrial morphology, biochemical assays assessed mitochondrial function, and ELISA estimated Aβ levels in the brain and muscle.

Results: Physical exercise improved locomotion, balance, and strength in advanced stages of the disease, with modest benefits for memory. Histology showed reduced muscle atrophy and cortical amyloid, but not hippocampal. ELISA detected lower relative levels of Aβ only in the brain. Exercise restored reduced muscle Complex I activity, increased brain Complex IV and ATPase in both tissues, and pronounced changes in mitochondrial morphology in muscle.

Conclusion: This study provides the first evidence that physical exercise improves motor function and attenuates muscle and brain pathology in advanced stages of 3xTg-AD, supporting its potential as a complementary therapeutic strategy with translational relevance to humans.

Objective: This study aimed to develop and preliminarily evaluate the feasibility of a home-based care program for family caregivers of individuals with Alzheimer's disease (AD).

Methods: We developed a home-based intervention for AD caregivers through systematic literature review and two-round Delphi consensus (18 experts; authority coefficients 0.88-0.91). This feasibility randomized controlled trial enrolled 61 primary caregivers and assigned them to either an experimental group (n=31) receiving a structured, evidence-based, 3-month home-care protocol, or a control group (n=30) receiving conventional nursing guidance.

Results: The Delphi process achieved strong expert consensus. Post-intervention, caregivers in the intervention group demonstrated significant improvements in AD knowledge scores, anxiety reduction, and psychological domain QOL-AD scores compared to baseline (P < 0.05). While total QOL-AD scores increased in the intervention group, between-group differences were not statistically significant.

Conclusion: The home-based care program proved feasible and effective in enhancing AD caregiver knowledge and mental health outcomes. These promising findings support the need for larger-scale efficacy trials to further validate clinical utility.

Introduction: Early diagnosis of neurodegenerative diseases remains a formidable challenge in modern neuroimaging, due to subtle and heterogeneous brain deterioration patterns in early disease stages. Integrating artificial intelligence and radiomic analysis has emerged as a powerful paradigm for non-invasive biomarker discovery and precision diagnostics. In alignment with trends emphasizing cross-modality analysis, interpretability, and demographic generalization, this study introduces a novel approach leveraging object detection and disentangled representation learning to improve early detection sensitivity and reliability. Traditional radiomics frameworks often suffer from limited generalizability, rigid feature engineering, and confounding variability from age, imaging protocol, or anatomical variations, undermining clinical robustness.

Methods: Our method addresses these limitations through a three-pronged strategy. We construct a hybrid representation framework separating age-related morphometric changes from disease-specific alterations. We introduce NeuroFact-Net, a dual-path variational encoder-decoder architecture supervised along anatomical and diagnostic axes, enhancing interpretability and facilitating trajectory analysis. Wedevise a Causal Disease-Aware Alignment (CDAA) strategy imposing population-level invariance and disease-specific consistency using contrastive learning, adversarial subgroup confusion, and maximum mean discrepancy constraints.

Results and discussion: Experiments across multi-site MRl and PET datasets demonstrate superior diagnostic accuracy, domain transferability, and latent biomarker interpretability, validating its potential for clinical deployment in early-stage screening. This work contributes a scalable, interpretable, and causally grounded computational framework aligned with Al-enhanced neuroimaging advancements.

Lactate is the terminal product of anaerobic oxidation within the glucose metabolism pathway. Traditionally, lactate has been regarded as a metabolically insignificant byproduct derived from incomplete oxidation. However, recent evidence suggests that lactate plays dual roles in the nervous system: neuroprotective and neurotoxicity. The diverse functions of lactate in the nervous system are influenced by its varying concentrations and distinct signal transduction pathways. This review focuses on elucidating the molecular mechanisms underlying lactate's functions through energy metabolism, neurodegeneration, neural excitation, and neuroinflammation, particularly the signaling pathways involved in neuroprotection and neuroinjury. Furthermore, we highlight several pharmacological agents associated with these processes, aiming to provide novel insights and therapeutic strategies for neuroprotection under specific conditions such as hypoxia, and the management of neurological disorders.

Background: Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons. Gamma-aminobutyric acid (GABA), as a key inhibitory neurotransmitter, participates in physiological processes such as cognition and motor control by regulating the balance of neuronal excitability. Related studies have found that the GABAergic signaling abnormalities in the basal ganglia and thalamocortical circuits are closely associated with the motor dysfunction and non-motor symptoms of PD. This study aimed to analyze GABA and PD research literature to further identify hotspots, frontiers, and development directions.

Method: Data were obtained from the Web of Science, Scopus, and PubMed databases. VOSviewer and CiteSpace were used to visualize and perform quantitative analyses.

Results: From 2001 to 2024, a total of 630 publications related to GABA and PD were identified, and the annual publication count fluctuated with an overall upward trend. The United States and China contributed a large number of publications. Karolinska Institute was the leading research institution. Neuroscience published the most papers related to GABA and PD. Dr. Morari, Michele was the most prolific author. The keywords with high frequency focused on the core pathological mechanisms and the imbalance of neurotransmitters, the neural anatomical structure and functional circuits, the main research methods and models, and the treatment strategies. In recent years, α-synuclein, oxidative stress, and anxiety have emerged as research topics with higher burst intensity.

Conclusion: This study delineates a comprehensive knowledge structure of GABA and PD research. Enhanced collaboration among authors across institutions and countries is pivotal to advancing the field. The mechanism of GABA in the basal ganglia region is a focus of current research. The detrimental effects of α-synuclein and oxidative stress on the GABAergic system and the non-motor symptom of anxiety are likely to be the frontiers of future research.

C-X3-C motif chemokine ligand 1 (CX3CL1), a structurally unique chemokine in the central nervous system (CNS), shapes physiological and pathological processes via specific binding to its receptor, C-X3-C motif chemokine receptor 1 (CX3CR1). Empirical evidence indicates that this signaling axis exerts dual neuroinflammatory effects: It restrains microglial hyperactivation, yet can promote inflammation under conditions such as chronic stress. Notably, it preserves synaptic plasticity and facilitates remyelination. Age-associated reductions in CX3CL1 exhibit a strong correlation with cognitive decline; administration of exogenous CX3CL1 partially mitigates these deficits. This study provides a comprehensive account of the multifaceted functions and regulatory mechanisms of CX3CL1 in CNS diseases, thereby establishing a basis for potential new therapeutic targets.