Investigating the role of p16 and cellular senescence in Alzheimer’s disease pathogenesis

ABSTRACT: Advancing age is the greatest risk factor for Alzheimer’s Disease (AD), as most AD patients are age 65 and older. However, the mechanistic contribution of aging to AD is unclear. Cellular senescence, one of the major hallmarks of aging, is recently implicated as an aggravator of AD pathogenesis. The critical senescence regulator p16 is increased in neurons of AD patients and mouse models. Eliminating p16-expressing senescent cells attenuates AD pathologies in AD mouse models. However, what p16 does in post-mitotic neurons and how p16 contributes to AD pathogenesis remains unknown. As clinical trials continually fail to improve cognitive decline in AD patients, it is increasingly important to develop a better human cell-based model system to advance our understanding of the impact of aging in AD pathogenesis. Induced pluripotent stem cell (iPSC) technology has revolutionized human disease modeling, enabling differentiation to relevant brain cell types for the study of AD pathogenesis in a human cell-based culture environment. AD iPSC-derived neurons exhibit higher levels of Amyloid beta secretion and tau phosphorylation compared to non-demented control iPSC-derived neurons. Nevertheless, iPSC-derived neurons are “fetal-like” and fail to recapitulate the aging process in AD pathogenesis. Thus, we have developed a robust human iPSC-based neuron model to investigate the contribution of p16 expression to cellular senescence and AD pathogenesis. We found that inducible p16 expression leads to senescence phenotypes in AD as well as non-demented control iPSC-derived neurons. The impact of p16 and induced senescence in neurons on the cellular pathologies of AD is investigated. Our study provides a novel approach to investigate aging-associated cellular changes that potentially influence AD patient-derived differentiated neurons to age and become more permissive to AD pathogenesis in culture.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252132 | GEO | 2023/12/31

REPOSITORIES: GEO