# Role of Senescent T cells in Alzheimer's Disease

> **NIH NIH R21** · SAINT LOUIS UNIVERSITY · 2020 · $285,918

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia, and also an age-related neurological
disorder. AD not only causes severe distress for patients and caregivers, but it also becomes a major public
health predicament. However, the mechanisms responsible for the pathogenesis of AD are still unclear, which
is a major challenge for AD prevention and therapy. Increasing evidence suggests that dysfunctional and aging
immune system may be a primary factor/inducer for the development of AD. Accumulated regulatory T (Treg)
cells and senescent T cells have been identified in AD patients, but the functional roles of these T cell
populations in the pathogenesis of AD are poorly understood. Furthermore, the causative relationship between
Treg and senescent T cells in AD development and progression is unknown. We recently discovered a novel
suppressive mechanism that human Treg cells can induce responder naïve and effector T cell senescence.
Importantly, our more recent studies demonstrated that senescent T cells can promote the aggregation of
amyloid precursor protein (APP), amyloid beta (Aβ) and Tau proteins in human neuronal cells. Therefore, an
improved understanding of the molecular and cellular processes of senescent T cells in the pathogenesis of
AD is urgently needed, which could lead to the development of novel and effective therapeutic strategies. The
central hypotheses of this proposal are: 1) accumulated Treg cells induce senescence among T cells thereby
promoting the development and pathogenesis of AD; 2) blockage of senescence in T cells is a critical
checkpoint to control AD pathologic processes and progression, which will provide a novel strategy for AD
prevention and immunotherapy. Specific Aim 1 seeks to determine whether senescent T cells induced by Treg
cells are a critical player for the pathogenesis of AD in vivo in animal models. Aim 2 will first investigate
whether and how senescent T cells reprogram the metabolism and functions of differentiated and
undifferentiated neuronal cells. We will then identify the unique senescence-associated secretory phenotype
(SASP) of senescent T cells, including inflammatory cytokines and metabolites, responsible for the functional
changes in neurons induced by senescent T cells, resulting in neurodegeneration and AD development. Aim 3
will further propose complementary in vivo studies to test our hypothesis and the novel concept that reversal of
T cell senescence through the inhibition of ATM signaling and/or MAPK signaling can prevent AD development
and mitigate AD pathology in a spontaneous senescence accelerated mouse model. A positive outcome of
these studies should lead to novel strategies for molecular control of T cell fate and function for AD prevention
and immunotherapy.

## Key facts

- **NIH application ID:** 9975395
- **Project number:** 1R21AG067441-01
- **Recipient organization:** SAINT LOUIS UNIVERSITY
- **Principal Investigator:** Guangyong Peng
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $285,918
- **Award type:** 1
- **Project period:** 2020-05-01 → 2023-02-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975395

## Citation

> US National Institutes of Health, RePORTER application 9975395, Role of Senescent T cells in Alzheimer's Disease (1R21AG067441-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9975395. Licensed CC0.

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