# Knockin Mouse Models of Alzheimer's Disease

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $565,122

## Abstract

Abstract
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder defined by the deposition of β-amyloid
(Aβ) plaques and accumulation of neurofibrillary tangles (NFTs), of which the principal components are Aβ
peptides derived from the amyloid precursor protein (APP) and hyper-phosphorylated Tau, respectively. The
relationship between the extracellular Aβ and intracellular NFT pathologies and how aging contributes to the
disease pathogenesis are critical questions but remain poorly understood. Besides the pathological hallmarks,
AD is associated with profound neuroinflammation marked by reactive astrogliosis and microgliosis. The
complement pathway is a well-recognized innate immunity modulator. We uncovered an astroglial C3 and
neuronal and microglial C3a receptor (C3aR) mediated neuron-immune signaling network that is prominently
elevated in human AD and in AD mouse models where inactivation of C3aR ameliorates AD pathology and
cognitive impairment. Since C3aR is widely expressed in the central nervous system, the C3aR blockade could
exert its beneficial effects by acting on these cell types individually or by influencing the neuron-immune
network. Indeed, crosstalk between microglia, astrocytes, and neurons has long confounded elucidation of
their individual roles in neuroinflammatory damage. To tackle this problem, we have created a C3ar1
conditional allele that allows us to inactivate the C3aR in different cell types in the CNS and delineate their cell-
type-specific roles. We have also developed a powerful technology that enables us to isolate high-quality RNA
and to perform RNA sequencing analysis from aged dissociated and fluorescence-activated cell sorting
(FACS) sorted individual neurons, astrocytes, and microglia. This affords unbiased analysis of central immune
and inflammatory pathways with unprecedented cellular specificity. Building on these exciting biological and
technical developments, we propose to a) decipher the role and cell-type-specific contribution of C3-C3aR
pathway in AD pathogenesis using APP knock-in mouse models; b) interrogate cell-type-specific changes as a
function of Aβ pathology and C3aR ablation and identify common signatures in human AD; c) determine the
cellular mechanisms underlying complement mediated Tau/NFT pathology. These will provide unprecedented
insights into the cell-type-specific targets in AD pathogenesis and we are equipped with innovative technology
and sophisticated mouse models to address these questions.

## Key facts

- **NIH application ID:** 9988984
- **Project number:** 5R01AG020670-19
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Hui Zheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $565,122
- **Award type:** 5
- **Project period:** 2002-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988984

## Citation

> US National Institutes of Health, RePORTER application 9988984, Knockin Mouse Models of Alzheimer's Disease (5R01AG020670-19). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9988984. Licensed CC0.

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