# Cell autonomous and non-autonomous mechanisms in Alzheimer's disease and related dementias

> **NIH NIH P01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2021 · $523,285

## Abstract

PROJECT SUMMARY
The goals of the Program Project are to understand the causes and consequences of cellular senescence as a
driver of age-related neurodegeneration, determine new targets and mechanisms by which senescent cells drive
disease, and identify new targets for interventions that alter disease onset and/or progression. Project 3 will
explore the cell-autonomous and non-autonomous mechanisms of cellular senescence in Alzheimer's
disease (AD) and related dementia. Senescent astrocytes and neurons displaying senescent-like changes
accumulate in the aging brain, and we hypothesize this is causative in AD. Recent work in Project 1 on mouse
models of Parkinsonism suggests cellular senescence plays a significant role in PD pathology and progression.
A role for senescence in AD is supported by the finding that senolytics (drugs that selectively kill senescent cells)
prevent AD pathology and behavioral phenotypes. We hypothesize that neurons in the brain adopt a cellular
senescent-like phenotype that contributes to AD. We will elucidate key senescent cell types in the brain and
their communication with residing cells that trigger the cascade of events and lead to AD in mouse and human
models of AD. Age-dependent and senescence-driven impairments of neuron function and their responses to
senescent astrocytes or microglia will be examined for their roles in the onset and progression of AD. Therefore,
we will examine proteinopathy-induced neuronal senescence and their response to senescent glia (astrocyte
and microglia). The following Specific Aims are proposed: Aim 1. Determine how neurons become senenscent
like and their response to senescent astrocytes or microglia; Aim 2. Determine if cellular senescence drives
pathology and behavioral phenotypes in mouse models of AD; and Aim 3. Model cellular senescent phenotypes
in human cerebral organoid models of AD. These studies will accelerate the discovery of senescence factors
and downstream targets that influence neurodegeneration and allow us to identify better therapeutics targets for
AD and related dementias.

## Key facts

- **NIH application ID:** 10187414
- **Project number:** 1P01AG066591-01A1
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Lisa M Ellerby
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $523,285
- **Award type:** 1
- **Project period:** 2021-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187414

## Citation

> US National Institutes of Health, RePORTER application 10187414, Cell autonomous and non-autonomous mechanisms in Alzheimer's disease and related dementias (1P01AG066591-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10187414. Licensed CC0.

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