Monday, February 16, 2026 2/16/2026

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

Award Number: R01AG075108
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $427,397 )
2026	2026	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	001	5	1/16/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$427,397
2026	2025	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	4	1/16/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $427,397

Issue Date FY: 2025 ( Subtotal = $465,388 )
2025	2025	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	001	4	8/11/2025	NON-COMPETING CONTINUATION	$37,991
2025	2025	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	4	11/29/2024	NON-COMPETING CONTINUATION	$427,397
														Subtotal = $465,388

Issue Date FY: 2024 ( Subtotal = $474,886 )
2024	2024	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	001	3	5/2/2024	NON-COMPETING CONTINUATION	$47,489
2024	2024	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	3	11/22/2023	NON-COMPETING CONTINUATION	$427,397
														Subtotal = $474,886

Issue Date FY: 2023 ( Subtotal = $474,886 )
2023	2023	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	2	1/5/2023	NON-COMPETING CONTINUATION	$474,886
														Subtotal = $474,886

Issue Date FY: 2022 ( Subtotal = $474,886 )
2022	2022	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	1	1/12/2022	NEW	$474,886
														Subtotal = $474,886

Grand Total All Awards = $2,317,443

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

Award Number: R01AG075108

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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