Biomarkers of Senescent Microglia in Neurodegenerative Disease Pathogenesis

Glial cells, particularly microglia, play an integral role in Alzheimer’s Disease (AD) by facilitating phagocytosis, which in turn helps limit the aggregation of amyloid-beta (Aβ) plaques and neurofibrillary tau tangles—two hallmarks of AD. However, the combination of aging and AD progression degenerates microglia into senescence. In this state, microglia secrete pro- inflammatory cytokines such as TNF-α and IL-1, contributing to disease progression rather than mitigating the effects of AD. Given this critical intersection between microglial senescence and AD pathology, a class of treatments designed to selectively eliminate senescent cells, known as senolytics, has emerged as a promising therapeutic strategy to slow and mitigate the effects of disease progression. However, it is essential that these senolytic agents minimize off-target effects on healthy brain tissue and do not result in indiscriminate cell elimination. Thus, our research seeks to utilize genetic mouse models and cell culture systems to investigate the nature of senescent microglia and identify associated markers. By targeting these markers, we aim to develop senolytic-based interventions to further develop effective treatment of AD and other age-related neurodegenerative diseases.