Authors
Annan Liu, Liping Xing, Jianhui Li, Wei Gao, Mingyuan Yao, Jing Song, Honglin Li
Published in
Ageing research reviews. Pages 103352. Sep 05, 2026. Epub Sep 05, 2026.
Abstract
Alzheimer's disease (AD) is an age-dependent neurodegenerative syndrome in which microglial senescence bridges biological ageing and Aβ-tau pathology. Senescent microglia undergo permanent cell-cycle arrest, upregulate p16INK4a and SA-β-gal, and secrete a pro-inflammatory senescence-associated secretory phenotype (SASP) that sustains chronic neuroinflammation. Mitochondria-endoplasmic reticulum contact sites (MERCS) are dynamic physical junctions between the endoplasmic reticulum (ER) and mitochondria, whereas mitochondria-associated membranes (MAM) are biochemically enriched ER subdomains located at MERCS. MERCS coordinate calcium shuttling, mitochondrial dynamics, lipid trafficking and the unfolded protein response (UPR); however, whether their dysfunction drives microglial senescence in vivo remains largely untested.
This review critically integrates five MERCS-linked signalling axes that are hypothesised to drive microglial senescence, namely calcium overload, mitochondrial fission-fusion imbalance, inflammatory amplification, lipid dysregulation and unresolved ER stress. We apply a standardized four-tier evidence-grading framework to stratify causal evidence, systematically distinguish dystrophic, disease-associated (DAM) and bona-fide senescent microglia on the basis of transcriptomic and proteomic data from AD models and human tissues, and address underexplored dimensions including APOE/TREM2 crosstalk, mitophagy, epigenetic regulation, peripheral inflammation and senolytic combinations. We stress that inflammatory activation, oxidative stress and mitochondrial dysfunction represent common cellular stress responses that cannot independently define bona-fide microglial senescence. Because more than 90% of current mechanistic evidence is derived from non-microglial models, MERCS dysfunction in microglia remains a compelling hypothesis that requires rigorous in-vivo validation. Notably, MERCS dysfunction and AD-relevant APOE/TREM2 signalling engage in mutually modulatory crosstalk rather than a simple linear upstream-downstream hierarchy.
Translational development faces several barriers, including poor blood-brain barrier (BBB) penetration, off-target neurotoxicity, uncharacterised long-term safety and limited generalisability from APP/PS1 models lacking tauopathy. All MERCS-targeted and senolytic combinatorial strategies discussed herein represent prospective pre-clinical research directions rather than mature clinical therapeutic approaches. We propose an experimental roadmap based on conditional knockouts, intravital imaging and bidirectional interventions. Overall, MERCS dysfunction is proposed as a candidate multimodal upstream hub for calcium, mitochondrial, inflammatory, lipid and ER-stress signalling, and rigorous in-vivo validation together with microglia-selective delivery platforms is essential for therapeutic translation.
PMID:
42700866
Bibliographic data and abstract were imported from PubMed on 06 Sep 2026.
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