# Mechanisms of axonal protection by astrocytes and microglia inAlzheimer disease

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $628,075

## Abstract

PROJECT SUMMARY
Microglia and astrocytes have long been suspected of participating in the pathogenesis of Alzheimer’s disease
(AD). However, it is not clear how these cells orchestrate their reactions in AD and whether they play protective
or deleterious roles that can be targeted therapeutically. We recently discovered a potentially neuroprotective
function that we termed the “microglia barrier”. We found that the robust encapsulation of Aβ deposits by
microglia processes cause Aβ aggregates to become compact, less toxic and insulated from adjacent neurites,
thereby reducing the formation of dystrophic axons. This neuroprotective function was severely disrupted in mice
lacking Trem2 or Dap12, which have defects in microglia polarization towards plaques, leading to a more diffuse
plaque conformation and worsening of axonal dystrophy. In this proposal, we aim to explore the possibility that
in addition to microglia, the astrocytic reaction to early amyloid aggregates and the coordinated reaction between
these two cell types is critical for the overall glial protective function. We will utilize sophisticated super-resolution
imaging of mouse and human brain, intravital optical imaging and in vivo single cell manipulations to investigate
the cellular and molecular basis of astrocyte and microglia orchestrated interactions and polarization towards
amyloid deposits. We will also explore signaling pathways that can be targeted to enhance this neuroprotective
glial barrier and reduce AD-associated axonal pathology.

## Key facts

- **NIH application ID:** 10549778
- **Project number:** 5R01AG074657-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jaime Grutzendler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $628,075
- **Award type:** 5
- **Project period:** 2022-01-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10549778

## Citation

> US National Institutes of Health, RePORTER application 10549778, Mechanisms of axonal protection by astrocytes and microglia inAlzheimer disease (5R01AG074657-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10549778. Licensed CC0.

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