# cGAS-STING  mediated neuroinflammation in Alzheimer's disease

> **NIH NIH R56** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $826,222

## Abstract

Abstract:
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) in plaques and
hyperphosphorylated tau in neurofibrillary tangles, as well as neurovascular dysfunctions and neuroinflammation,
which together result in neurodegeneration and cognitive impairment. Both clinical and preclinical studies have
indicated that neuroinflammation, particularly abnormal and chronic microglia activation, is a major part of AD
etiology. Innate immunity is the first line of host defense against invading pathogens and harmful substance. It
consists evolutionarily conserved pattern recognition receptors, including Toll-like receptors on the cell surface
and intracellular vesicles, and nucleotide sensors such as cyclic GMP-AMP synthase (cGAS) for cytosolic DNA.
The activation of these innate signaling pathways triggers the production of inflammatory cytokines and
interferons, and further amplifies the immune response by activating a large array of interferon-stimulated genes.
Interestingly, the innate immune responses are not always specific, and can often be activated by host molecules
in injuries and diseases; however, their contributions to neuroinflammation and AD pathogenesis in aging remain
underexplored.
Our central hypothesis is that chronic activation of innate immunity in microglia is a fundamental underlying
mechanism for neuroinflammation, which can be collectively triggered by amyloid and/or infections, and cGAS-
STING mediated innate immunity is a critical biological process in the development and progression of AD. Our
preliminary studies showed that cytosolic dsDNA levels were increased in AD post-mortem brain samples and
5xFAD mouse model, which is tightly associated with cGAS-STING pathway activation. More importantly, cGAS
knockout mice ameliorated the neuroinflammation and amyloid pathologies in the 5xFAD model, which can be
mimicked by a treatment with STING inhibitor H-151. For a better understanding of cGAS-STING pathway in AD,
we now propose to study: 1) cGAS-STING dependent modulation of neuroinflammation in vitro using a tri-cellular
culture system with iPSC-derived cells, and AD pathogenesis in animal models with cGAS and STING inhibitions;
2) the impact of herpes simplex virus (HSV-1) infection on cGAS-STING pathway and neuroinflammation using
iPSC-derived brain organoid models including cerebral and choroid plexus organoids, at signaling and
transcriptomic levels; 3) the effect of HSV1 infection on AD-like pathogenesis in EOAD and LOAD mouse models.
Through these studies, we hope to achieve an in-depth understanding of the cGAS-STING innate immune
pathway in CNS infection, inflammation and AD pathogenesis, and provide new insights into the infectious
etiology of AD and related dementia (ADRD).

## Key facts

- **NIH application ID:** 10900996
- **Project number:** 1R56AG082361-01A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Weiming Yuan
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $826,222
- **Award type:** 1
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900996

## Citation

> US National Institutes of Health, RePORTER application 10900996, cGAS-STING  mediated neuroinflammation in Alzheimer's disease (1R56AG082361-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10900996. Licensed CC0.

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