Wednesday, December 17, 2025 12/17/2025

Promotion of Alzheimers Disease by Alcohol - Role of eCIRP

Award Number: R01AA028947
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Promotion of Alzheimers Disease by Alcohol - Role of eCIRP - PROJECT DESCRIPTION: The goal of this R01 proposal is to investigate a novel molecular mechanism by which extracellular cold-inducible RNA-binding protein (eCIRP), released from microglial cells upon alcohol exposure, leads to tau pathology in Alzheimer’s disease (AD). AD is the 6th leading cause of death in the US and the most common form of neurodegenerative dementia. Although studies link heavy alcohol drinking to AD, the underlying mechanisms have not been sufficiently explored. We have shown that eCIRP is a critical mediator of memory impairment induced by exposure to binge-drinking levels of alcohol, leading us to postulate that eCIRP may be a key player in the relationship between alcohol and AD. Indeed, we discovered that eCIRP was increased in the cerebrospinal fluid of AD patients. We also showed that alcohol increased the brain levels of eCIRP in an animal model of binge alcohol drinking, and that microglial cells are the probable source of eCIRP in the brain after alcohol exposure. Moreover, eCIRP increased tau phosphorylation and upregulated the Cdk5 hyperactivator p25 via the direct binding to and activation of the interleukin-6 receptor α (IL-6Rα)/STAT3 pathway. Based on these novel findings, we hypothesize that alcohol-induced microglial cell- derived eCIRP activates the neuronal IL-6Rα/STAT3/Cdk5 pathway, leading to pathological tau phosphoryl- ation and aggregation. We also showed that the CIRP-derived peptide C23 effectively inhibited the activation of the IL-6Rα/STAT3/Cdk5 pathway induced by eCIRP. Therefore, we further hypothesize that treatment with C23 attenuates the development of alcohol-induced tau pathology. In this project, we plan to further establish the role of alcohol-induced microglial cell-derived eCIRP in pathological tau phosphorylation and aggregation. We will then elucidate the molecular mechanism through which eCIRP produces AD-like pathological tau phosphorylation and aggregation. Finally, we will examine whether inhibition of eCIRP with C23 attenuates tau phosphorylation and aggregation after exposures to binge-drinking levels of alcohol. These studies will provide novel pivotal insights into the mechanisms responsible for the influence of heavy alcohol drinking on the pathogenesis of AD, as well as a new potential therapeutic strategy to treat AD patients in the future.


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 = $0 )
2026	2024	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Alcohol Research Programs	000	5	12/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $418,750 )
2024	2024	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Alcohol Research Programs	000	5	8/7/2024	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2023 ( Subtotal = $418,750 )
2023	2023	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Alcohol Research Programs	000	4	8/21/2023	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2022 ( Subtotal = $418,750 )
2022	2022	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Alcohol Research Programs	000	3	8/24/2022	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2021 ( Subtotal = $418,750 )
2021	2021	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Alcohol Research Programs	000	2	8/23/2021	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2020 ( Subtotal = $418,750 )
2020	2020	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Alcohol Research Programs	000	1	9/16/2020	NEW	$418,750
														Subtotal = $418,750

Grand Total All Awards = $2,093,750

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Promotion of Alzheimers Disease by Alcohol - Role of eCIRP

Award Number: R01AA028947

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/20/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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