# Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients

> **NIH NIH RF1** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2024 · $109,805

## Abstract

Project Summary: Alzheimer’s disease (AD) affects over 50 million people worldwide1. For the vast majority
of patients, AD is sporadic, with no known etiology other than advanced age. The field of neuroscience has
understandably focused on cell intrinsic properties of neuronal cells as the basis for neurodegenerative
diseases, such as AD. However, about half of the cells in the brain are glial cells with ~15% of cells in the brain
accounted for by microglia2. Microglia are specialized macrophages of the central nervous system that help to
clear debris, pathogens, and neuronal synapses. Under homeostatic conditions, microglia provide support to
neurons, while under pathological conditions, microglia often prune synapses excessively, activate astrocytes,
increase inflammation, and reduce support to neurons3. Currently, a mechanistic understanding of microglia in
Alzheimer’s disease (AD) is unclear. To advance the scientific goals of aim 4, this project will study metabolic
neuron-microglia interactions in three-dimensional multicellular cultures. This project will test the hypothesis
that aberrant neuronal PKM2 challenges neuron-glia coupling, and that the microglial capacity to prune and
respond to inflammatory stimuli is influenced by their APOE (Apolipoprotein E) haplotype. The original proposal
indicated that astrocyte activation may be lacking in the absence of microglia to properly activate them. Since,
significant advances have been made in the Gage lab to address this issue through the incorporation of
microglia into organoids (In press, Cell. May 2023), which will complement the microcarrier data and provide a
separate piece of evidence. Metabolic changes in glia by APOE haplotype is well documented4,5, but the
impact on neurons is less clear. It is unknown how APOE ε4 allele influences AD onset and progression or how
APOE ε2 allele provides protection6. This lab has recently acquired commercially available human isogenic
iPSC lines that have been genetically altered to represent each APOE haplotype. Microglia will be generated
from each of these lines as previously described7 and cultured in multi-cell microcarriers and organoids.
Preliminary data from this lab suggests that microglia with APOE4/4 have AD related metabolic defects
associated with lipid metabolism, lysosomal and mitochondrial function. The goal of this project is to analyze
the transcriptome and functionality of microglia with different APOE haplotypes. By employing single cell RNA
sequencing, this project will identify differences in gene expression on a cell-type basis, between these groups.
These data will contribute to the overall proposal and reveal specific genes involved implicated in AD and age-
related lysosomal function and metabolism are downregulated by APOE. Through this mechanism, APOE4
microglia may actively contribute to the pathogenesis of AD, rather than solely reacting to AD pathogenesis.
The hypothesis of this project is that APOE4 microglia will exhibi...

## Key facts

- **NIH application ID:** 11082927
- **Project number:** 3RF1AG056306-06S2
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** FRED H GAGE
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $109,805
- **Award type:** 3
- **Project period:** 2017-07-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11082927

## Citation

> US National Institutes of Health, RePORTER application 11082927, Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients (3RF1AG056306-06S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11082927. Licensed CC0.

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