# Metabolic Control of T Cell Senescence in Pathogenesis and Immunotherapy of Alzheimer's Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $388,750

## 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 senescent T cells
have been identified in both AD patients and in aged AD onset mice, but the causative relationship between
the increased senescent T cells and 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. Senescent T cells exhibit active lipid metabolism and possess a unique senescence-associated
secretory phenotype (SASP), producing high amounts of lipids and metabolites. 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 senescent T cells with excessive lipid metabolism promote the development and
pathogenesis of AD; and 2) blockage of senescence in T cells via lipid reprogramming 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 with lipid metabolism disorder
are a critical driver for the pathogenesis of AD. We will dissect the causative role of the secretory lipid
metabolites of senescent T cells in reprogramming functions of neuronal cells. We will also identify the
molecular and metabolic signaling responsible for the functional changes in neurons induced by senescent T
cells, resulting in neurodegeneration and AD development. Specific Aim 2 will propose complementary in vivo
studies to identify the causative relationship between the accumulated senescent T cells and AD development
and disease progression in a spontaneous senescence accelerated SAMP8 mouse model. We will then test
our hypothesis and the novel concept that that reprogramming of T cell lipid metabolism to reverse T cell
senescence is a novel strategy to prevent AD development and enhance efficacy for AD immunotherapy. A
positive outcome of these studies should lead to novel strategies for metabolic control of T cell fate and
function for AD prevention and immunotherapy.

## Key facts

- **NIH application ID:** 10888418
- **Project number:** 5R01AG078822-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Guangyong Peng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888418

## Citation

> US National Institutes of Health, RePORTER application 10888418, Metabolic Control of T Cell Senescence in Pathogenesis and Immunotherapy of Alzheimer's Disease (5R01AG078822-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10888418. Licensed CC0.

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