# mtDNA leakage and STING-dependent microglial innate immune response in Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF KANSAS LAWRENCE · 2022 · $474,886

## Abstract

PROJECT SUMMARY
Characterized by progressive cognitive decline, Alzheimer's disease (AD) is the most common type of dementia,
primarily affecting the aging population. Inflammatory activation of microglia is an early pathological feature of
Alzheimer’s disease (AD) and contributes to brain damages. However, the underlying mechanisms that mediate
microglial inflammatory activation in Aβ-rich milieus are not completely understood. Stimulator of interferon
genes (STING) is an innate immune adaptor protein that is abundantly expressed by cells of myeloid origin
including microglia. Despite its roles in interferon-based antiviral immunity, recent studies have revealed an
important contribution of STING signaling to inflammatory damages in non-communicable disorders. cyclic GMP-
AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor and signals through STING to promote interferon
signaling and production of inflammatory mediators. Cytosolic accumulation of endogenous DNA especially
mitochondrial DNA (mtDNA) fragments constitutes an important source of endogenous “sterile” activator of
cGAS-STING signaling. In our preliminary study on patients and an AD animal model with AD-like
amyloidopathy, we observed increased microglial STING activity, which contributed to early microglial activation
in 5xFAD mice. In addition, microglia from patients and 5xFAD mice demonstrated cytosolic mtDNA
accumulation; and deficiency of cGAS attenuated microglial STING activation in 5xFAD mice, implicating an
association of cytosolic mtDNA sensing by cGAS with STING activation. Finally, our data suggest that microglial
mitochondrial stress in Aβ milieus may contribute to mtDNA instability and leakage into the cytosol. We therefore
hypothesize that microglial STING signaling triggered via cytosolic mtDNA sensing by cGAS contributes to Aβ-
induced microglial activation, culminating in neuroinflammation and neuronal stress in AD. Here, we aim to
establish a link between microglial STING activity and microglial activation in 5xFAD mice. Next, we will
determine the contribution of microglial STING activation to microglial deregulation-associated brain damages
in 5xFAD mice. In addition, we will address the mechanisms that mediate microglial mtDNA release in Aβ-rich
milieus and determine the importance of mtDNA leakage for the activation of microglial cGAS-STING signaling
in Aβ-rich milieus. Taken together, the results from this study will answer important questions about STING in
shaping microglial phenotype, and will suggest a novel mitochondrial mechanism of microglial activation and
new avenues for the treatment of AD.

## Key facts

- **NIH application ID:** 10346449
- **Project number:** 1R01AG075108-01
- **Recipient organization:** UNIVERSITY OF KANSAS LAWRENCE
- **Principal Investigator:** Heng Du
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $474,886
- **Award type:** 1
- **Project period:** 2022-01-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10346449

## Citation

> US National Institutes of Health, RePORTER application 10346449, mtDNA leakage and STING-dependent microglial innate immune response in Alzheimer's disease (1R01AG075108-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10346449. Licensed CC0.

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