# Mechanisms of Age-Related Microglial Impairment and Rejuvenation in Alzheimer's Disease

> **NIH NIH F30** · STANFORD UNIVERSITY · 2020 · $45,232

## Abstract

Project Summary
Age is the main risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder rapidly increasing in
both incidence and prevalence as the population becomes older. Unfortunately, AD is the only top ten cause of
death with no effective treatments. Therefore, the development of disease-altering treatments for AD is an
urgent and unmet need. Although the exact etiology of AD is unknown, microglia, the tissue-resident
macrophages of the brain, have been implicated in disease pathogenesis based on the observation that
genetic variants in several microglia-specific genes significantly alter disease risk. In the healthy brain,
microglia maintain homeostasis through multiple modalities including phagocytic clearance of pathogens,
apoptotic cells, and debris. In AD brains and age-matched clinically-unimpaired brains alike, microglia are
dystrophic, hypo-motile, and burdened with lysosomal deposits indicative of impaired phagocytic degradation
of debris. These findings suggest that the general decline in phagocytosis with age might underlie pathological
neurodegeneration. However, the mechanisms of age-related microglial dysfunction are poorly understood.
This proposal aims to elucidate the mechanisms of impaired microglial phagocytosis in the aging brain and to
uncover therapeutic strategies to reverse this impairment in AD. Preliminary data suggest that cell-surface
sialic acid, an immunomodulatory glycan modification, inhibits phagocytosis in aged microglia. Aim 1 combines
biochemical and genetic tools to identify upstream and downstream signaling partners that transduce the anti-
phagocytic effect of sialic acid on aged microglia. Aim 2 will evaluate the therapeutic potential of blocking the
interaction between cell-surface sialic acid and its cognate receptor on microglia to promote phagocytosis and
ameliorate cognitive decline in a mouse model of AD. These experiments will elucidate a mechanism of
microglial dysfunction during normal aging with direct translational implications for patients with AD.

## Key facts

- **NIH application ID:** 9947844
- **Project number:** 5F30AG060638-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** John Vincent Pluvinage
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,232
- **Award type:** 5
- **Project period:** 2018-08-02 → 2021-08-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9947844

## Citation

> US National Institutes of Health, RePORTER application 9947844, Mechanisms of Age-Related Microglial Impairment and Rejuvenation in Alzheimer's Disease (5F30AG060638-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9947844. Licensed CC0.

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