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Astrocytic exocytosis of ATP in amyloid pathology and Alzheimer's disease

Award Number: R03AG083363
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Astrocytic exocytosis of ATP in amyloid pathology and Alzheimer's disease - Contact PD/PI: Cai, Weikang Project Summary/Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disease with no cure. It is characterized by β- amyloid (Aβ)-containing senile plaques and tau-containing neurofibrillary tangles in the brain. Among many mechanisms contributing to AD, excessive deposition of toxic Aβ peptides is considered to play a key role. Recent studies have demonstrated that Aβ deposition in the brain triggers robust morphological and transcriptomic changes in astrocytes. How these alterations of astrocyte functions may contribute to the development of AD remains unclear. The preliminary studies of the PI’s research group show that Aβ42 induces ATP release in cultured astrocytes. Further, loss of vesicular nucleotide transporter (Vnut), which is responsible of loading cytosolic ATP into the excretory lysosomes, in astrocytes dramatically reduces Aβ plaques by ~50% and improved cognitive function in 6-month-old female 5xFAD mice. These data strongly suggest that elimination of ATP exocytosis in astrocytes blocks the accumulation of amyloid plaques and alleviates the cognitive decline. With the strong support of these exciting preliminary data, the proposed research hypothesize that Aβ deposition enhances astrocytic exocytosis of ATP, and chronic elevation of astrocyte-derived ATP further induces neuroinflammation, impairs Aβ production and clearance, and exacerbates cognitive decline. The proposed research will address this central hypothesis in specific aims: Aim 1: To examine the dynamic interaction between astrocytic exocytosis of ATP and Aβ deposition. Briefly, microdialysis will be used to assess how extracellular ATP levels in the brain are altered when Vnut is deleted in astrocytes in response to Aβ deposition. The reduced Aβ deposition could be due to decreased production or increased clearance. To this end, the relative contents of APP products, including soluble APPα, Aβ40, and Aβ42 will be quantified to assess the preference of Aβ production. In addition, Aβ-associated astrocytes and microglia will be quantified as an indicator of glial-dependent Aβ clearance. Aim 2: To assess the contributions of the astrocytic exocytosis of ATP on neuroinflammation in mouse models of AD. Neuroinflammation in 5xFAD mice without astrocytic Vnut will be examined using immunoblotting, immunofluorescence, qPCR and ELISA, and compared to appropriate control mice. In addition, to explore additional contributing mechanisms, the transcriptomes of astrocytes of these mice will be analyzed using RNA Seq and bioinformatics. Throughout the project, all the data on neuroinflammation, the extracellular ATP levels, and Aβ deposition will be correlated with the learning and memory of the same mice at 6 and 12 months of age. With a novel genetic mouse model, the proposed research will provide valuable insight into the roles of astrocytes and purinergic signaling in AD. This will help generate key preliminary data to support a more in-depth investigation in a future R01 grant. In the long term, this line of research may reveal new therapeutic approaches to treat AD and possibly other neurodegenerative diseases, by targeting purinergic signaling. Project Summary/Abstract Page 6


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 = $0 )
2025	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	2	10/17/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2023	NEW YORK INSTITUTE OF TECHNOLOGY	1855 BROADWAY	NEW YORK	NY	10023	NEW YORK	USA	Aging Research	001	1	12/4/2024	NEW	$0
2025	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	002	2	8/26/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	001	2	7/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$207,000
2024	2023	NEW YORK INSTITUTE OF TECHNOLOGY	1855 BROADWAY	NEW YORK	NY	10023	NEW YORK	USA	Aging Research	000	1	7/11/2024	NEW	-$207,000
2024	2023	NEW YORK INSTITUTE OF TECHNOLOGY	1855 BROADWAY	NEW YORK	NY	10023	NEW YORK	USA	Aging Research	002	1	7/24/2024	NEW	$20,000
2024	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	003	2	7/24/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$20,000
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $306,000 )
2023	2023	NEW YORK INSTITUTE OF TECHNOLOGY	NORTHERN BLVD	OLD WESTBURY	NY	11568	NASSAU	USA	Aging Research	000	1	8/31/2023	NEW	$306,000
														Subtotal = $306,000

Grand Total All Awards = $306,000

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Astrocytic exocytosis of ATP in amyloid pathology and Alzheimer's disease

Award Number: R03AG083363

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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