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Maladaptive antiviral pathways in Alzheimer's disease

Award Number: R01AG072758
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Maladaptive antiviral pathways in Alzheimer's disease - ABSTRACT Alzheimer's disease (AD) is the most common form of late-onset dementia. The extents of tau pathology are closely related to memory decline. How pathogenic tau causes cognitive deficits is not clear. While most studies on tau have been focused on direct effects of tau on neurons, compelling human genetic studies linked maladaptive innate immune responses, including microglial responses, to elevated risk of developing late- onset Alzheimer disease. The striking enrichment of innate immune genes as risk alleles for Alzheimer disease supports critical disease-enhancing role of maladaptive microglia in tau-mediated cognitive deficits. Identifying how maladaptive microglial enhances tau toxicity could lead to new therapeutic strategies. In our preliminary studies, we found that tauopathy mice exhibit hyperactive Cyclic GMP-AMP synthase (cGAS)- Stimulator of interferon genes (STING) signaling. As a major sensor of cytosolic DNA, cGAS-STING pathway mobilizes antiviral responses via activation of interferon regulatory factors (IRFs) and expression of cytokine and type I interferon genes. The hyperactive cGAS pathways contributes to tau toxicity since genetic reduction of cGAS protected against tau-mediated spatial learning and memory deficits in a tauopathy mouse model of Alzheimer disease. In addition, the protective effects were associated with reduced interferon-enriched microglial subpopulations and reprogramming of disease-associated microglial states as identified using single nuclei RNA-seq. We hypothesize that microglial cGAS-STING hyperactivation mediates the maladaptive disease-enhancing microglial response in tauopathy. To test this hypothesis, In Aim 1, we will first determine how cGAS activation in microglia enhances tau toxicity (1a). Using a combination of single nuclei RNA-seq, pathological and functional analyses, we will investigate if toxicity from cGAS hyperactivation in microglia or bone marrow-derived monocytes (1b, 1c). In Aim 2, we will dissect if the toxic effects of cGAS activation in tauopathy are mediated by STING-dependent or -independent mechanisms, we will determine if loss of STING phenocopies the effects of cGAS inactivation on tau toxicity and transcriptomic changes (2a). We will then determine STING-independent mechanisms of cGAS activation by assessing how cGAS inactivation affects tau toxicity on Sting null background (2b). The significant protective effects of partial loss of cGAS supports that partial inhibition with pharmacological inhibitors of cGAS could be beneficial for tauopathy. We showed that a specific cGAS inhibitor, TDI6570, is brain permeable and effectively inhibit expression of type 1 interferon target genes in tauopathy mice. We will then optimize the dosing using formulated chow based on PK/PD, and evaluate the beneficial effects of the cGAS inhibitor before or after the onset of cognitive deficit in tauopathy mice in Aim 3. Completion of the proposed study will identify novel disease-enhancing properties of innate immune responses in AD, and provide new therapeutic direction for pharmacological intervention.


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 = $799,148 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	001	5	6/10/2025	NON-COMPETING CONTINUATION	$65,238
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	000	5	3/20/2025	NON-COMPETING CONTINUATION	$733,910
														Subtotal = $799,148

Issue Date FY: 2024 ( Subtotal = $810,371 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	000	4	4/18/2024	NON-COMPETING CONTINUATION	$810,371
														Subtotal = $810,371

Issue Date FY: 2023 ( Subtotal = $834,101 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	3	3/15/2023	NON-COMPETING CONTINUATION	$834,101
														Subtotal = $834,101

Issue Date FY: 2022 ( Subtotal = $830,711 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	2	4/4/2022	NON-COMPETING CONTINUATION	$830,711
														Subtotal = $830,711

Issue Date FY: 2021 ( Subtotal = $830,711 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	1	6/8/2021	NEW	$830,711
														Subtotal = $830,711

Grand Total All Awards = $4,105,042

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Maladaptive antiviral pathways in Alzheimer's disease

Award Number: R01AG072758

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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