# Contribution of a novel OPN-producing CD11c+ microglial subset to AD

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2024 · $505,974

## Abstract

Summary
We have recently identified a small subset of CD11c+ microglia as the sole producer of OPN (Osteopontin; Spp1)
and major disease driver in the 5XFAD mouse model of Alzheimer’s Disease (AD). Our analysis of OPN-
producing CD11c+ microglia has divided Disease-Associated Microglia (DAM) that surround Aβ plaques into two
opposing subsets that together regulate AD pathology. A pathogenic CD11c+OPN+ microglial subset promotes
proinflammatory responses and drives AD development, and a protective CD11c+OPN− microglial subset
degrades Aβ fibrils and inhibits disease pathology. We find that genetic deletion of OPN (a) inhibits microglial
proinflammatory responses, (b) enhances TREM2/TAM-dependent uptake and lysosomal breakdown of Aβ
plaques and (c) markedly improves cognitive function. Analyses of clinically and neuropathologically
characterized brain tissue from AD patients and controls (Mt. Sinai Brain Bank and the Rush Alzheimer’s Disease
Study) confirm these murine findings. In addition, administration of α-OPN mAb markedly ameliorates the
microglial proinflammatory responses and reduces Aβ plaques in 5XFAD mice.
Here we propose Osteopontin (OPN) as a novel and tractable target based on preclinical studies of the 5XFAD
model of Alzheimer’s disease (AD) (performed at DFCI) and analysis of well-characterized human brain tissue
(performed at Mt. Sinai and Rush Alzheimer’s Disease Center) (Aims 1 and 2). We also test the therapeutic
impact of mAb-based approaches that target OPN in the 5XFAD mouse model in Aim 3. The overarching goal
of our therapeutic approaches is conversion of proinflammatory microglia into a non-inflammatory phenotype
with enhanced ability to engulf and digest Aβ fibrils. Identification of a pathogenic (CD11c+OPN+) microglial
subset in both murine and human brain tissue provides new insight into the pathogenic pathway that may drive
clinical AD and a foundation for the development of therapeutics that target this pathology and halt or reverse
disease progression.

## Key facts

- **NIH application ID:** 10807320
- **Project number:** 1R01AG075837-01A1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** HARVEY CANTOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $505,974
- **Award type:** 1
- **Project period:** 2024-02-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807320

## Citation

> US National Institutes of Health, RePORTER application 10807320, Contribution of a novel OPN-producing CD11c+ microglial subset to AD (1R01AG075837-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10807320. Licensed CC0.

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