# Investigating CD33 function on microglia during Alzheimer’s disease using CRISPR nanoparticles

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $425,625

## Abstract

Abstract
Microglia, the immune cells of the brain, are key cellular players in the pathogenesis and progression of
Alzheimer’s disease (AD). As the immune cells of the brain, microglia are the cell type predominantly involved
in phagocytosis of protein aggregates such as amyloid b (Ab), which aggregates to form the characteristic
plaques present in AD. A decrement of microglia phagocytic capability, combined with a pro-inflammatory
phenotype, may lead to a brain environment permissive for Ab plaque formation. Recent genome-wide
association studies have identified mutations in the immune-cell specific gene CD33, expressed almost
exclusively on microglia in the brain, as a risk factor for development of AD. CD33 is a member of the Siglec
family of receptors, and has an immunosuppressive effect upon detection sialic acids. Reduced expression of
CD33 is protective against formation of Ab plaques by stimulating phagocytosis and altering pro-inflammatory
phenotype in microglia. Thus, CD33 represents an important therapeutic target for treatment and prevention of
AD. However, an appropriate timepoint for anti-CD33 treatments has not been established due to technical
challenges with manipulating CD33 in the brain of transgenic animal models of AD. Here, we propose to use a
brain- and microglia-validated method for delivery of CRISPR to the brain to knock down expression of CD33 at
various times during the course of disease progression in a transgenic animal model of AD. We predict that
downregulation of CD33 early and late in disease will differentially alter microglia phagocytosis of Ab, change
plaque load, abrogate neurotoxicity, and improve memory deficits. Further, we aim to understand the
heterogeneity of microglia CD33 expression in human AD patients by examining existing single-cell
transcriptomics datasets. We predict that microglia with reduced CD33 will display a phagocytic and
neuroprotective gene signature. We predict that this gene signature will also be evident in CD33-high and CD33-
low microglia from transgenic AD mice. Finally, we will test sialic acid binding as a potential mechanism by which
CD33 regulates phagocytosis of Ab. Overall, these studies will enhance our current understanding of how CD33
modifies microglia function in vivo and will elucidate the benefits of early (preventative) vs. late (interventional)
CD33 knockdown which will inform potential future treatments of CD33-targeting therapeutics.

## Key facts

- **NIH application ID:** 10211028
- **Project number:** 1R21AG072423-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Sarah Christine Hopp
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $425,625
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10211028

## Citation

> US National Institutes of Health, RePORTER application 10211028, Investigating CD33 function on microglia during Alzheimer’s disease using CRISPR nanoparticles (1R21AG072423-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10211028. Licensed CC0.

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