Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities

• Published in: Neuroprotection (Chichester, England. Online) England. Online), 2024-09, Vol.2 (3), p.182-195
• Main Authors: Olajide, Tobiloba Samuel, Oyerinde, Toheeb O., Omotosho, Omolabake I., Okeowo, Oritoke M., Olajide, Olayemi J., Ijomone, Omamuyouwi M.
• Format: Article
• Language: English
• Subjects: aging; ferritin; microglia; neurodegenerative diseases; senescence‐associated secretory phenotype; senescent
• ISSN: 2770-7296; 2770-730X; 2770-730X
• DOI: 10.1002/nep3.56

The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression. Recent research has linked disease‐associated microglia to their transition into a senescent state—characterized by irreversible cell cycle arrest—in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease‐associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets. This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age‐related NDDs. Microglial senescence plays a critical role in increasing susceptibility to neuronal degeneration. This study highlights that aging and the proteinopathies characteristic of various neurodegenerative diseases contribute to the induction of microglia senescence. Therapeutic strategies involving iron chelators and senolytics may hold promise for managing age‐related neurodegenerative diseases. IL, interleukin; SA‐β‐gal, senescence‐associated β‐galactosidase; SASP, senescence‐associated secretory phenotype; TNF, tumor necrosis factor. Highlights Significant findings of the study This study highlights the distinct contribution of microglial senescence to the pathophysiology of neurodegenerative diseases. What this study adds This study provides a comprehensive update on microglial