# Neuronal senescence and inflammation in Alzheimer's disease

> **NIH NIH R37** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2021 · $1,425,000

## Abstract

Project Summary
Age is the single strongest predictive factor for Alzheimer's disease (AD). The vast majority of AD cases arise
sporadically in the seventh decade of life or beyond, with no known etiology aside from advanced age. To
understand cellular and molecular changes at the root of AD, studies need experimental methods that discrim-
inate healthy from pathological aging. Until now, options for in vitro study of aged human neurons, the cell type
devastated by AD, have been lacking. This proposal will use induced neurons (iNs), a method that generates
neurons from fibroblasts by direct transdifferentiation, to study the cellular processes in neuronal aging and
AD. Unlike induced pluripotent stem cell (iPSC)-derived neurons, which pass through a stem cell intermediate
phase and become physiologically rejuvenated, iNs retain age-related features of their source fibroblasts.
Gene expression, epigenetic marks, and cell metabolism in iNs correspond to the age of the donor. Using the
iN system, this proposal will evaluate the interaction between two age-correlated factors associated with the
AD brain: cellular senescence and inflammation. Preliminary data demonstrate that iNs from AD patients are
more likely to show protein markers of senescence and upregulation of senescence-associated genes than iNs
from healthy aged controls (CTL). In Aim 1, senescent and non-senescent cells from AD and CTL Iines will be
examined by RNA-Seq and ATAC-Seq. These analyses will identify pre-existing differences in non-senescent
AD neurons that differentiate them from CTL as well as specific components of cellular senescence that are
unique to neurons, a cell type in which the existence of senescence remains controversial. In other tissues,
senescent cells release inflammatory factors (collectively termed the senescence associated secretory pheno-
type or SASP) that disrupt the local environment, contributing to age-related tissue dysfunction. In Aim 2, the
ability of secreted factors from AD and CTL iNs to activate human astrocytes and microglia will be assessed.
These experiments will generate a list of neuronal components of the SASP and identify which are contributors
to the chronic inflammation that arises with AD. Finally, Aim 3 will examine cellular processes hypothesized to
be upstream of senescence. Prior work and preliminary data show that AD and CTL iNs differ in their cellular
metabolism and intracellular nucleotide pools. The nucleotide content of AD and CTL iNs will be compared,
and small molecules will be used to manipulate components of nucleotide synthesis or salvage and test the
resulting impact on senescence. These studies will reveal whether inherent differences in nucleotide metab-
olism lead to increased rates of cellular senescence and contribute to the inflammatory response. As a whole,
these studies will provide novel insights into how senescence and inflammation interact within the aged
neuronal environment that is permissive to AD.

## Key facts

- **NIH application ID:** 10213563
- **Project number:** 1R37AG072502-01
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** FRED H GAGE
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,425,000
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213563

## Citation

> US National Institutes of Health, RePORTER application 10213563, Neuronal senescence and inflammation in Alzheimer's disease (1R37AG072502-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213563. Licensed CC0.

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