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Investigating the role of cGAS signaling and microglial senscence in tauopathy

Award Number: K99AG078493
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/05/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Investigating the role of cGAS signaling and microglial senscence in tauopathy - PROJECT SUMMARY Innate immune antiviral pathways are upregulated in Alzheimer’s disease (AD) and are thought to drive AD pathogenesis. The specific mediators of maladaptive antiviral responses in AD are still not understood. Innate immune system utilizes a series of nucleic acid sensors to detect viral genetic material to activate interferon expression. The central DNA sensor in the cell is cyclic GMP-AMP synthase (cGAS). cGAS signaling has emerged as an important player in many neurodegenerative diseases like Parkinson’s disease and amyotrophic lateral sclerosis. The role of cGAS signaling in tau-mediated neurodegeneration remains unstudied. We discover that cGAS signaling is hyperactivated in the brains of mice expressing mutant tau (P301S mice) and human AD patients. Using behavioral assays, electrophysiological readings and single nuclei RNA sequencing, our preliminary results indicate that cGAS activity modifies both the cellular responses to and the functional deficits caused by tauopathy. We observed that partial or complete loss of Cgas rescued tauopathy-associated spatial learning and memory deficits. cGAS is highly enriched in immune cells including microglia. We find that tau induces a cGAS-dependent interferon signature by triggering mitochondrial DNA stress in microglia and show that Cgas deletion alters microglial disease transformation, characterized by reduced expression of interferon genes in disease microglia. It is not known how tau can alter mitochondrial and nuclear dynamics to activate cGAS and how cGAS activation enhances neurotoxic effects of tau. This proposal will investigate the mechanisms and consequences of cGAS and nucleic acid sensing pathways in tauopathy. I aim to dissect the molecular mechanism of cGAS activation in response to tau by focusing on tau dependent cellular processes that induce mitochondrial stress and microglial senescence (Aim 1) and investigate how cGAS mediates maladaptive microglial responses and neuronal damage in tauopathy (Aim 2). Finally, since antiviral responses could be species-specific, there is strong rationale to extend mouse studies of innate nucleic acid sensing to human models. Human and mouse cGAS share only 60% amino acid similarity and have different activation requirements. I will establish human pluripotent stem cell (hPSC)-based platforms to study broader nucleic acid sensing pathways and perform unbiased CRISPR-screens to identify novel regulators of human nucleic acid sensing in tau toxicity (Aim 3). The experiments outlined in this proposal will lead to a better understanding of the role of nucleic acid sensors in tauopathy and AD which might prove translatable to humans.


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: 2025 ( Subtotal = $75,600 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	000	2	11/11/2024	SUPPLEMENT FOR EXPANSION	$75,600
														Subtotal = $75,600

Issue Date FY: 2024 ( Subtotal = $125,431 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	000	2	7/23/2024	NON-COMPETING CONTINUATION	$125,431
														Subtotal = $125,431

Issue Date FY: 2023 ( Subtotal = $125,431 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	1	8/4/2023	NEW	$125,431
														Subtotal = $125,431

Grand Total All Awards = $326,462

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Investigating the role of cGAS signaling and microglial senscence in tauopathy

Award Number: K99AG078493

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/05/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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