CLEARANCE OF SENESCENT CELLS IMPROVES COGNITIVE FUNCTION AND PLAQUE-RELATED PATHOLOGY IN THE APP<SUP>NL-G-F </SUP>MOUSE MODEL OF ALZHEIMER’S DISEASE

The global rise in life expectancy and increasing prevalence of Alzheimer’s disease (AD), represent a significant public health burden. Age-dependent accumulation of senescent cells has emerged as a potential contributor to neurodegenerative diseases. Cellular senescence is defined by permanent cell cycle arrest and the development of a senescence-associated secretory phenotype (SASP), which promotes chronic inflammation. In AD, senescence-associated inflammation is proposed to exacerbate amyloid-β and tau pathology, thereby intensifying neuroinflammatory responses. These observations have raised interest in senolytic strategies as potential disease-modifying interventions. In this study, we investigated the effects of senolytic treatment in APP^NL-G-F mice, a well-established model of amyloid pathology, to assess whether senescent cell clearance alleviates amyloid burden and cognitive impairment. Six-month-old mice received long-term senolytic treatment followed by behavioral, histological and transcriptomic analyses. Treated mice exhibited improved anxiety-related behavior and enhanced short- and long-term recognition memory. Histological analyses demonstrated a significant reduction in senescence markers, including SA-β-galactosidase, within the cortex. Amyloid pathology was markedly reduced, with fewer diffuse and dense-core plaques observed in both cortical and hippocampal regions. While astrocytes remain unchanged, oligodendrocyte density was reduced in the hippocampus. Overall microgliosis was diminished and homeostatic microglia reduced in the hippocampus. Notably, plaque-associated microglia remained unaffected, suggesting selective modulation of microglial subpopulations. Ongoing hippocampal RNA sequencing aims to identify treatment-associated transcriptional changes, particularly within inflammatory pathways. Collectively, these findings support a contributory role for cellular senescence in amyloid-driven pathology and highlight senolytic therapy as a potential approach to mitigate AD-related neuropathology and cognitive decline.