# The Role of the Complement Pathway in Alzheimer's Disease

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $780,898

## Abstract

Abstract
The development of -amyloid (A) pathology in Alzheimer’s disease (AD) is accompanied by hyperactivation
of microglia and neuroinflammation. Genome-wide association studies established a causal role of microglia in
AD pathogenesis. Microglia cluster around Aβ plaques to form a protective barrier and are also responsible for
Aβ uptake and clearance. These processes are energy intensive and require the expression and remodeling of
cell-surface proteins. Microglia under chronic Aβ exposure become reactive displaying less phagocytic
capacity. Increasing evidence implicates impaired metabolic and lipid homeostasis as key contributors to
microglia dysfunction. The complement pathway is a conserved innate immune modulator. The central
complement component C3 and its C3a receptor (C3aR) are elevated in the brains of AD patients and mouse
models and their inactivation confers protection against age-associated functional decline and AD
neuropathology, suggesting that inhibiting this pathway may provide therapeutic benefit against AD. Our recent
study of complement signaling identified Hypoxia Inducible Factor 1α (HIF-1α), which is an essential molecule
in oxygen sensing and metabolic reprogramming, as a downstream effector of C3aR mediating microglia
metabolism, A receptor trafficking and phagocytosis. Accordingly, understanding the role of HIF-1α in
regulating microglia metabolic state and identifying microglia cell-surface receptors in response to A
pathology are major objectives of the current proposal. Interestingly, besides C3a, C3aR also binds to TLQP-
21, a neuropeptide derived from VGF, which has been nominated as a key driver in AD by the Accelerating
Medicines Partnership for Alzheimer’s Disease (AMP-AD) consortium. However, little is known about the
relationship between the TLQP-21-C3aR and C3a-C3aR pathways. Thus, another goal of the application is to
decipher C3a and TLQP-21 mediated C3aR interaction. Overall, these studies will achieve an insightful
understanding of the two distinct ligands yet both implicated in AD, complement C3a and neuropeptide TLQP-
21, in C3aR signaling and microglia regulation. In addition, it will establish a mechanistic and functional link
between microglia metabolism and neuroinflammation through the C3aR-HIF-1α immunometabolic pathway
and provide proof-of-concept of targeting C3aR and HIF-1α as potential immune-based therapeutic strategy
through boosting microglia bioenergics and metabolic adaptive capacity. Lastly, it will identify new Aβ induced
microglia cell-surface receptors for therapeutic targeting.

## Key facts

- **NIH application ID:** 10939086
- **Project number:** 1R01AG088197-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Hui Zheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $780,898
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939086

## Citation

> US National Institutes of Health, RePORTER application 10939086, The Role of the Complement Pathway in Alzheimer's Disease (1R01AG088197-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10939086. Licensed CC0.

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