# Dissecting the impact of senescence pathways on the cellular pathogenesis of Alzheimer's disease

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $460,625

## Abstract

PROJECT SUMMARY
Recent studies showed that cellular senescence plays a critical role in the pathogenesis of Alzheimer’s disease
(AD). Senescent cells are detected in the brains of AD patients and mouse models of AD. Selective elimination
of senescent cells genetically or pharmacologically reduces neurodegenerative pathologies and ameliorates
cognitive deficits in AD mouse models. However, the underlying mechanism by which senescence contributes
to AD pathogenesis is not known. It is also unclear which brain cell types are the primary drivers of senescence-
dependent neurodegeneration. The goal of this project is to gain a mechanistic understanding of the role of
senescence in AD pathogenesis. Cellular senescence is highly heterogeneous, and the characteristic features
of senescent cells vary significantly upon various senescence-inducing stimuli, cell types and the stages of
senescence. Despite the heterogeneity of senescence, various senescence-inducing stimuli converge on two
major senescence pathways, the p53/p21 and the p16/pRb pathways, which can independently activate
senescence. In this proposal, we will dissect these two senescence pathways separately to uncover their
functional consequence in the cellular pathogenesis of AD using human induced pluripotent stem cell (iPSC)-
based AD models. Patient-derived iPSCs have revolutionized disease modeling and AD-related cell pathologies
have been recapitulated in neurons differentiated from AD-iPSCs. It has been suggested that neurons in AD
patients are prone to senescence and senescent neurons constitute most senescent cells in the brains of AD
patients. Further, genetic regulation and physiological consequence of senescence in post-mitotic cells such as
neurons are greatly understudied, as most studies focus on cells capable of proliferation. Towards our goal, we
have generated two inducible systems to activate the p53/p21 and the p16 pathways independently in human
iPSCs in a controllable and synchronized manner. The inducible approach allows temporal control for isogenic
comparisons of the same cell populations over the course of differentiation of iPSCs to neurons with and without
the activation of a specific senescence pathway. This strategy minimizes experimental heterogeneity associated
with differentiated cultures and provides a tighter control for inter-line variations. In Aim 1, we will focus on the
p53/p21 pathway activated by telomere dysfunction and its impact on senescence and AD cellular pathogenesis
in differentiated cortical neurons and cerebral organoids. In Aim 2, we will investigate the role of the p16 pathway
in senescence and AD cellular pathogenesis in neurons and cerebral organoids. This project will produce broadly
valuable cellular resources for senescence and AD research and provide new insight into senescence’s role in
AD pathogenesis.

## Key facts

- **NIH application ID:** 10870871
- **Project number:** 1R21AG086894-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Hong Zhang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $460,625
- **Award type:** 1
- **Project period:** 2024-09-30 → 2026-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10870871

## Citation

> US National Institutes of Health, RePORTER application 10870871, Dissecting the impact of senescence pathways on the cellular pathogenesis of Alzheimer's disease (1R21AG086894-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10870871. Licensed CC0.

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