CHRONIC SENOLYTIC TREATMENT MODULATES COGNITIVE PERFORMANCE AND GLIAL RESPONSE IN MOUSE MODELS OF ALZHEIMER’S DISEASE AND ACCELERATED AGEING

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, with ageing as its primary risk factor. Cellular senescence, a stable and irreversible cell cycle arrest, contributes to both ageing and AD pathology. Senescent cells accumulate in the ageing brain and secrete pro-inflammatory cytokines and proteases, potentially exacerbating neuroinflammation, cognitive decline and neurodegeneration. Targeting cellular senescence therefore represents a promising therapeutic strategy for AD-related dementia and brain ageing.

In this study, we investigated the effects of a senolytic treatment using two complementary mouse models: 5xFAD mice, a transgenic model of familial AD carrying five mutations in the amyloid precursor protein (APP) and presenilin-1 (PS1) genes, and SAMP8 mice, which exhibit accelerated ageing, cognitive impairment, and neuroinflammation. Five-month-old mice from both models received an intermittent senolytic treatment for two months. Cognitive performance was assessed using a battery of behavioural tests evaluating anxiety, working memory, and recognition memory. Senescence, plaque pathology and gliosis-related markers were analysed using immunohistochemistry and colorimetric imaging. Behavioural analyses revealed significant cognitive improvements in both models following the treatment. Neurochemically, senescence-associated β-galactosidase (SA-β-Gal) levels were unchanged, but a decrease of plaque burden and lysosomes were observed in 5xFAD mice specifically in the hippocampus dentate gyrus, as well as a modulation of microglial states. In the same brain area, the treatment modulated microglial and oligodendroglial phenotypes in SAMP8 mice.

These findings highlight the role of glial cells in response to AD and ageing, and support the potential of senolytic therapies in alleviating cognitive decline and mitigating neuroinflammation.