Frontiers in Aging Neuroscience最新文献

Alzheimer's disease (AD), a pressing global public health challenge, is underpinned by multifaceted pathogenic mechanisms. While traditional research has centered on amyloid-β deposition and tau hyperphosphorylation, emerging evidence reveals that metabolic perturbations play a pivotal role in the earliest phases of AD. As the principal regulators of energy homeostasis within the central nervous system, astrocytes orchestrate a multistep metabolic cascade-encompassing glucose uptake, glycolysis, mitochondrial oxidative metabolism, and the release of metabolic intermediates-to sustain neuronal energy supply and synaptic integrity. In the AD milieu, this astrocytic metabolic cascade becomes profoundly disrupted at every level. Such metabolic dysregulation not only compromises the neuroprotective functions of astrocytes but also directly accelerates synaptic degeneration, exacerbates Aβ and tau pathologies, and amplifies neuroinflammatory responses, collectively forming a core "metabolic-neurodegeneration" pathological axis. Here, we provide a comprehensive synthesis of the aberrant astrocytic metabolic cascade in AD, delineating its critical contributions to synaptic deterioration, proteinopathy progression, and inflammatory escalation. Building on these insights, we propose a conceptual model of an "astrocyte-centric metabolic collapse," highlighting metabolic derailment as a fundamental initiating and amplifying force in AD pathogenesis. Furthermore, we evaluate therapeutic strategies targeting key nodes of this cascade and discuss the challenges and opportunities inherent in modulating astrocytic metabolism. Through integrating the most recent advances, this review offers a refined understanding of astrocytic metabolic dysregulation in AD and examines its potential as a promising avenue for therapeutic intervention.

Alzheimer's disease (AD) research has transcended the traditional paradigm centered on amyloid-beta (Aβ) shifting toward a neuroimmune network perspective. This article systematically elucidates the evolving mechanisms underlying disease progression, from neuroimmune interactions to intercellular communication. Studies indicate that microglial and astrocytic dysfunctions are key contributors to disease progression, operating within a complex multifactorial framework. Upon transformation into disease-associated microglia (DAM), microglia exhibit a significant decline in Aβ clearance capacity and release a plethora of pro-inflammatory factors, exacerbating neuroinflammation and neuronal damage. Concurrently, astrocytes lose their homeostatic support functions and acquire neurotoxic properties. Intercellular communication molecules play pivotal roles as key mediators. The cytokine/chemokine network sustains a chronic inflammatory milieu; extracellular vesicles (EVs) facilitate the propagation of Aβ and tau pathologies; and the complement system (e.g., C1q) transitions from physiological synaptic pruning to pathological synaptic engulfment. Furthermore, peripheral immune cell infiltration and gut-brain axis dysregulation further expand the pathological scope. Consequently, therapeutic strategies are evolving towards multi-target interventions, including precise immune modulation (e.g., TREM2 agonists), exosome-based drug delivery systems, and combination therapies. Addressing disease heterogeneity and developing personalized treatments are critical future directions. Ultimately, early interventions aimed at restoring healthy intercellular communication offer new hope for halting AD progression.

Introduction: TAS2R38 is a taste receptor gene located on human chromosome 7 that influences sensitivity to bitter tastes and has been implicated in innate immunity, glucose level, and human longevity. However, its potential association with Alzheimer's Disease (AD) has not been explored. Identifying such a genetic connection could support developing new drugs or repurposing existing ones for AD treatment.

Methods: In this work, we examined the relationship between allele counts of TAS2R38 taster variants and AD risk using linear mixed-effects models, utilizing genetic, clinical, and biomarker data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We investigated the potential molecular mechanisms of the association by identifying expression quantitative trait loci (eQTLs) using RNA-seq data from postmortem tissues across brain regions from the Religious Orders Study/Memory and Aging Project (ROSMAP). We evaluated whether FDA-approved drugs targeting the identified e-gene could reduce dementia risk using 1:1 propensity score-matched groups from longitudinal data in the National Alzheimer's Coordinating Center (NACC) study, by comparing clinical dementia progression trends between the drug-taking and non-taking groups with linear mixed-effects models.

Results: Our results show that TAS2R38 supertasters were connected to a reduced AD risk with advancing age due to its association with various AD biomarkers (p < 0.001). eQTL analysis linked the nontaster allele to increased expression of the gene MGAM in AD-affected brain regions (p < 0.001). Furthermore, elevated MGAM expression correlated with more severe Tau burden (p < 0.05) and implicated in mitochondrial dysfunction in AD subjects. Notably, MGAM is a known drug target for diabetes mellitus. In NACC data, individuals taking MGAM-inhibiting drugs (acarbose and miglitol) showed slower clinical dementia rating progression (p < 0.01) in comparison with the non-taking group.

Discussion: This study is the first to report a genetic association between TAS2R38 and AD biomarkers. Our findings, validated in multiple cohorts/matching groups, suggest MGAM as a novel AD drug target with existing FDA-approved inhibitors and demonstrate the potential of TAS2R38 haplotypes to inform precision drug repurposing strategies for AD, which warrants further in-depth preclinical and clinical studies.

The global challenge of population aging underscores the critical need to delay brain aging and cognitive decline, a pressing public health issue. The brain-gut-muscle axis is a complex regulatory network connecting skeletal muscle, gut microbiota, and the brain. It has received considerable research attention for its crucial role in maintaining brain health and counteracting aging. As a safe and effective non-pharmacological intervention, exercise modulates gut microbiota composition and diversity and promotes the secretion of myokines from skeletal muscle. These actions, in turn, influence neural plasticity, inflammatory responses, and cognitive function. This review summarizes the mechanisms mediated by exercise within the brain-gut-muscle axis. We focus on: (1) how exercise dynamically regulates gut microbiota; (2) the interplay between myokines and gut microbiota; (3) the neuroprotective role of myokines; and (4) the potential mechanisms of the brain-muscle and gut-muscle pathways. Finally, we integrate these findings to present a synthesized view of how exercise delays brain aging through the brain-gut-muscle axis.

Background: Parkinson's disease (PD) entails widespread neurodegenerative changes extending beyond motor symptoms to cognitive and large-scale network alterations that compromise functional autonomy. Financial abilities (FAs) are complex, ecologically relevant skills crucial for independent living, yet their neurocognitive and neurofunctional substrates in PD remain largely unexplored. This study investigates the cognitive, structural, and neurofunctional correlates of basic and advanced FAs in PD with mild cognitive impairment (PD-MCI), using voxel-based morphometry to identify structural brain changes associated with FAs and resting-state network analyses to elucidate how brain connectivity supports preserved financial functioning.

Methods: Thirty three individuals with PD-MCI completed a comprehensive neuropsychological assessment, including the Numerical Activities of Daily Living-Financial Short battery, to evaluate basic and advanced FAs. A subset of patients (n = 24) underwent acquisition of 3T structural and resting-state functional neuroimaging data. To identify cognitive and neural predictors of basic and advanced FAs, multiple regression models incorporating demographic covariates, cognitive and neuroimaging predictors were employed via stepwise Akaike Information Criterion and LASSO procedures.

Results: Basic FAs were associated with general cognition and formal numerical competence (i.e., arithmetic knowledge), alongside negative functional correlations between somatomotor and subcortical networks. Advanced FAs were associated with different cognitive functions, such as executive ones, informal numerical competencies (i.e., use of numbers in everyday life), social cognition, language, and memory, and were linked to cerebellar network dynamics, specifically, increased anti-correlation with salience and limbic systems and enhanced synchronization with frontoparietal and subcortical circuits.

Discussion: FAs in PD-MCI rely on a dynamic balance between network specialization and compensatory integration, reflecting adaptive reorganization of cortico-subcortical and cerebellar systems that may sustain complex cognitive functioning and functional independence.

Background: Age-related changes in the neuromuscular and sensory systems compromise the control of balance and stability. Static balance assessments may overlook deficits that appear when coping with unexpected perturbations. This cross-sectional study aimed to compare static and dynamic balance performance in younger and older adults to assess age-related differences in postural control between the two age groups.

Methods: Sixty-nine younger adults (24.3 ± 0.4 years) and sixty-one older adults (72.1 ± 0.6 years) performed balance assessments under static and dynamic conditions on a force platform. Center of pressure (CoP) was calculated during quiet standing for static balance and during an unexpected perturbation of the base of support for dynamic balance. In the perturbation-based task, the following CoP-related parameters were analyzed within a 2.5-s window from perturbation onset: displacement (Area95D), Mean VelocityD, anterior-posterior first peak (FP), post-perturbation variability (PPV), and maximal oscillations (ΔCoPMax). Sample Entropy (SampEn X and Y) was computed to infer the automaticity of postural control.

Results: In the static test, balance performance did not differ between younger and older adults, although older adults exhibited reduced efficiency (p < 0.05). Dynamic balance showed age-related differences, with older adults highlighting larger Area95D (p < 0.001), higher Mean VelocityD (p < 0.001), and greater FP (p < 0.05). SampEn X did not differ between groups, whereas SampEn Y was lower in older adults (p < 0.001).

Conclusion: Age-related changes in balance control are task dependent. Older adults preserved static balance performance but demonstrated impaired reactive balance responses in dynamic tasks. Furthermore, static and dynamic balance rely on distinct control mechanisms, highlighting the need for separate assessments.

Introduction: Although high inspired oxygen fraction (FiO₂) is used during anesthesia to prevent hypoxemia, the effect of different oxygen fraction on the brain remains unclear. This study aims to evaluate whether different inspired oxygen fractions (FiO₂ 30% vs. 80%) during anesthesia affect inflammation and antioxidant enzyme activity in the cortex and hippocampus of young and aged mice.

Methods: Young and old mice were anesthetized with sevoflurane at FiO₂ 30% or 80% for 3 h. Mice in the control group were exposed to medical air (FiO₂ 21%) for 3 h. Cytokine and superoxide dismutase (SOD) assays were performed on the cortex and hippocampus samples after anesthesia.

Results: The IL-1β level in the hippocampus was significantly higher in the FiO₂ 80% group compared with controls [5.0 (4.0-6.9) pg. mL^-1 vs. 2.3 (1.6-2.7) pg. mL^-1; adjusted p = 0.032], whereas no significant differences were observed in IL-1β levels between the control and FiO₂ 30% groups [adjusted p = 0.164] or the FiO₂ 30% and FiO₂ 80% groups [adjusted p = 0.390]. Except for IL-1β in the hippocampus, no significant differences in the cytokine levels and SOD activities were observed among the groups according to the inspired oxygen fraction in either brain region or age group [p > 0.05].

Discussion: Only 80% oxygen increased hippocampal IL-1β compared with controls, suggesting region-specific vulnerability to oxygen-induced neuroinflammation. However, no significant differences between FiO₂ levels (30% vs. 80%) indicate a limited neuroinflammatory impact under 3 h of anesthesia. Further studies with longer exposure and surgical conditions are needed to clarify the clinical implications.

Background: Anticholinergic side effects of pharmacological treatment are a risk factor for cognitive decline in older people. Here, we aimed to assess the effect of anticholinergic burden of treatment on longitudinal rates of cognitive change and atrophy in functionally related brain regions in people from the Alzheimer's disease (AD) spectrum.

Methods: We determined associations of anticholinergic burden of pharmacological treatment with rates of global cognition, episodic memory and executive function decline as well as basal forebrain and hippocampus atrophy in participants of the memory clinic based DELCODE cohort, spanning the range from cognitively normal through subjective cognitive decline, mild cognitive impairment and AD dementia. We had 794 cases with neuropsychological outcomes, and a subset of 703 cases with MRI outcomes. Effects were assessed using mixed effect models in a Bayesian framework using prior-insensitive cross-validated Bayes factors (CV-BF) and parameter estimates.

Results: We found moderate evidence for an association of anticholinergic burden with baseline levels of cognitive impairment for the PACC5 as a global cognitive function score (CV-BF = 9.0) with more impairments with higher burden, but not with basal forebrain and hippocampus volumes, and weak evidence for an association of anticholinergic burden with longitudinal rates of change in the trail-making test B as an executive function score (CV-BF = 2.5), but not for other cognitive scores and not for brain volumes.

Conclusion: In the presence of prodromal or manifest AD, in a memory clinic-based cohort anticholinergic burden had only a modest effect on cognitive decline and no effect on atrophy in brain regions that are related to the cholinergic system.

[This corrects the article DOI: 10.3389/fnagi.2025.1559647.].

Background: Deep cervical lymphovenous anastomosis (DCLVA) has been proposed as a novel surgical strategy to promote brain waste clearance in Alzheimer's disease (AD), inspired by advances in glymphatic and meningeal lymphatic research. Early reports suggested possible cognitive benefits, yet the scientific basis of this approach remains controversial.

Discussion: This Perspective critically examines the mechanistic rationale, anatomical limitations, and methodological shortcomings underlying DCLVA. The pressure disparity between cervical lymphatic and venous systems challenges the physiological feasibility of the procedure, while existing studies lack randomized design, biomarker validation, and control for anesthesia-related confounding. Ethical and translational considerations further underscore the need for rigorous preclinical and clinical evaluation before any clinical adoption.

Summary: While DCLVA reflects an innovative attempt to translate lymphatic biology into surgical therapy, its current theoretical and empirical foundation is insufficient. A shift toward mechanistic validation, objective imaging biomarkers, and non-invasive modulation of lymphatic function is warranted before DCLVA can be considered a viable therapeutic option for AD.