# Modulating Polarization of Glial Cells in AD mouse models by a Complement Receptor Antagonist

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $193,125

## Abstract

By 2050 it is estimated that there will be 13.8 million individuals in the US with Alzheimer's
disease (AD), at a cost of over $1.2 trillion per yr, if no disease-modifying therapy is developed.
The relative contributions of the AD defining pathological markers, amyloid and
hyperphosphorylated tau, to cognitive dysfunction remains controversial, but studies in both AD
patients and transgenic mouse models of AD, have shown that amyloid is necessary but not
sufficient for the development of cognitive loss which is the key clinical target of AD. There is a
growing consensus that it is the response of glial cells in the brain to amyloid that is relevant to
neuronal damage and thus cognitive impairment. The capacity of these cells to phagocytose
and clear amyloid and perhaps other deleterious material in the brain may have a substantial
influence on the initiation and progression of the disease. The complement cascade, a powerful
effector mechanism of the immune system that is directly activated by fibrillar Aβ (fAβ), can both
enhance clearance and induce inflammation. In addition, complement activation dependent
excessive synapse pruning occurs in models of AD and other neurological disorders, and is
postulated to contribute to the loss of cognition. Our data demonstrate that pharmacologic
inhibition or genetic deletion of C5aR1, a receptor for the complement activation
proinflammatory fragment, C5a, suppresses cognitive loss in mouse models of Alzheimer's
disease/amyloidosis. This study proposes to investigate the effect of a C5a receptor antagonist
on inflammation- and clearance-related gene expression (using single cell RNA-seq to evaluate
multiple cell types affected), protein expression and synaptic density (via super resolution
microscropy) in order to determine if C5aR1 plays a direct or indirect role in neuronal damage
and whether C5aR1 antagonists may be promising therapeutic candidates for future clinical
trials in humans to prevent cognitive impairment.

## Key facts

- **NIH application ID:** 9856405
- **Project number:** 5R21AG061746-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Andrea Joan Tenner
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,125
- **Award type:** 5
- **Project period:** 2019-02-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856405

## Citation

> US National Institutes of Health, RePORTER application 9856405, Modulating Polarization of Glial Cells in AD mouse models by a Complement Receptor Antagonist (5R21AG061746-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856405. Licensed CC0.

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