# Determining the neuroprotective mechanism for microglial autophagy in Alzheimer's disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $843,612

## Abstract

Our central goal is to determine neuroprotective mechanism conferred by microglia and autophagy, and
understand how dysfunctional autophagy in microglia contributes to the pathogenesis of Alzheimer's disease
(AD). Emerging evidence from human genetic and pathological studies has demonstrated the significance of
microglia pathophysiology in the pathogenesis of AD. Microglia are the resident innate immune cells in the
brain. The exact role for microglia in AD pathogenesis, however, remains poorly understood. Multiple lines of
studies revealed the protective function of microglia that restrain the toxic accumulation of β-amyloid and
prevent disease progression. However, evidence also exists suggesting excessive microglial activation can
harm the neurons by releasing inflammatory factors and engulfing neuronal synapses. Microglia may
phagocytose Aβ, the main component of plaques as a hallmark of AD pathology; single-cell RNAseq analysis
showed the disease-associated microglia (DAM), which localizes at plaques in AD animal models, consistent
with a role of TREM2 as a critical regulator of DAM activation. Autophagy is a lysosome clearance pathway
that plays an important role in maintaining homeostasis under metabolic stress and neuroprotection. Little is
known about glial autophagy. Previous studies from peripheral immune cells demonstrate a significant role of
autophagy in immunity and inflammation. Whether microglial autophagy plays such a role, however, remains
poorly understood. We recently analyzed AD mouse model and observed the activation of microglial
autophagy. We found that DAM is associated with a robust increase of autophagic activity. We also showed
that inactivation of microglial autophagy causes reduced number of microglia associated with Aβ plagues and
enhanced neurotoxicity in AD models, which phenocopied the effect of the loss of Trem2 in AD models.
Therefore, our overall hypothesis is that autophagy activation is required for DAM metabolic fitness to degrade
Aβ and protect neurons in the AD brains. We also hypothesize that microglial autophagy controls inflammation
by selective degradation of inflammasomes via protein receptors that are neuroprotective in AD. Our specific
aims are to (1) determine the role for microglial autophagy in neuroprotection by clearing phagocytosed Aβ and
maintaining metabolic fitness in AD mouse models; (2) dissect the mechanism of microglial autophagy that
controls inflammation in AD mouse model; (3) determine that autophagy is an integral part of TREM2-mediated
neuroprotection mechanism in microglia of AD mouse model.

## Key facts

- **NIH application ID:** 10213290
- **Project number:** 1R01AG072520-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Zhenyu Yue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $843,612
- **Award type:** 1
- **Project period:** 2021-06-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213290

## Citation

> US National Institutes of Health, RePORTER application 10213290, Determining the neuroprotective mechanism for microglial autophagy in Alzheimer's disease (1R01AG072520-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213290. Licensed CC0.

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