# Defining the Mechanistic Link between C5aR1 signaling and cognitive loss in Alzheimer's diseases

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $662,270

## Abstract

Project Summary:
 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, and that the capacity 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. Our data demonstrate that pharmacologic inhibition or genetic deletion of
C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppresses neurite
and cognitive loss in mouse models of Alzheimer's disease/amyloidosis. The effects of blocking this
C5a receptor interaction on astrocyte activation, inflammatory and clearance related gene
expression, neuronal integrity and synaptic density are proposed in two aims here with the ultimate
goal of determining mechanistic steps between activation of C5aR1 and loss of neuronal function, as
well as the potential for C5aR1 antagonists as therapeutic candidates for clinical trials in humans to
prevent cognitive impairment. In a third aim, we proposed to use a newly generated mouse with a
floxed C5aR1, to temporally and cell specifically ablate the receptor and assess gene expression,
neuronal integrity and function in an AD mouse model, to more closely mimic the adult inhibition of
this receptor that would occur with receptor antagonist treatment of individuals with or at risk for AD.
Selective modulation of complement activation products or their receptors may be an optimal strategy
for retaining the neuroprotective and phagocytic functions of complement components, as well as
systemic protection from pathogens lysis, while dampening induced inflammatory damage.
Importantly, blockage of this ligand-receptor system has not shown adverse effects in humans,
suggesting that C5aR1-targeted therapeutics for AD may be safely administered.

## Key facts

- **NIH application ID:** 10213622
- **Project number:** 5R01AG060148-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Seyed Ali Mortazavi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $662,270
- **Award type:** 5
- **Project period:** 2018-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213622

## Citation

> US National Institutes of Health, RePORTER application 10213622, Defining the Mechanistic Link between C5aR1 signaling and cognitive loss in Alzheimer's diseases (5R01AG060148-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10213622. Licensed CC0.

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