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Characterization of amyloid-β:α7β2-nicotinic acetylcholine receptor interactions relevant to Alzheimer's disease

Award Number: R21AG067029
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2023

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Characterization of amyloid-β:α7β2-nicotinic acetylcholine receptor interactions relevant to Alzheimer's disease - Alzheimer's disease (AD) is a neurodegenerative condition characterized by relentlessly progressive cognitive decline. There is no cure or effective treatment, especially given futility in preserving cognitive function in AD patients using interventions to remove amyloid-β (Aβ) plaques previously considered to be pathological hallmarks of disease. However, attention has turned to potential etiopathogenic roles of soluble, oligomeric forms of Aβ (oAβ). Moreover, remaining relevant is the loss of basal forebrain cholinergic neurons (BFCN) that provide widespread innervation to other brain centers critical for normal cognitive performance. A long-term goal of our work related to AD is to identify seminal and early disease processes that lead to BFCN functional instability and degeneration and can be targeted early enough to slow or stop neuronal death and memory compromise. Our preliminary findings support and merge aspects of both the oAβ and cholinergic hypotheses of AD. They show that sustained exposure in murine organotypic culture to oAβ causes hyperexcitation and eventual death of BFCN. These effects are blocked by antagonists of nicotinic acetylcholine receptors containing α7 subunits (α7*-nAChR). They also are absent for BFCN from nAChR β2 subunit knock-out mice. nAChR α7 and β2 subunits are enriched in BFCN where they combine to form a unique α7β2-nAChR subtype distinct from homomeric receptors composed of α7 subunits alone (α7-nAChR). Furthermore, deficits in spatial reference memory in an AD mouse model is normalized if those mice also lack β2 subunits. Most critical to this exploratory R21 project is our finding that oAβ mimics acetylcholine (ACh) in the ability to activate α7- and α7β2-nAChR single channel function. oAβ, but not ACh, uniquely alters single channel kinetics only for α7β2-nAChR. These studies support the project's overarching hypothesis that oAβ action at α7β2-nAChR leads to observed instability and demise of BFCN and ultimate cognitive compromise. This developmental project's goals are to identify sites for oAβ:α7β2-nAChR interactions and ways to prevent them without perturbing natural activation of α7β2-nAChR by ACh. Specific Aim 1 is to test the hypothesis that the site for human oAβ stimulation of human α7β2-nAChR function is different than that for ACh action as an agonist. Specific Aim 2 is to test the hypothesis that fragments of Aβ can block effects of oAβ at α7β2-nAChR while leaving ACh agonist action intact. Our proven skills will be used in nAChR expression, site-directed mutagenesis, pharmacology, and single channel electrophysiology. Results will provide a molecular description of oAβ:α7β2-nAChR interactions that lead to BFCN demise and could explain the emergence of dementia. These events occur early enough in disease progression to allow for novel therapeutic interventions to prevent or abate neuronal loss and useful, timely 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: 2024 ( Subtotal = -$45 )
2024	2021	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Aging Research	000	3	1/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$45
														Subtotal = -$45

Issue Date FY: 2022 ( Subtotal = -$50,762 )
2022	2021	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Aging Research	000	2	3/29/2022	NON-COMPETING CONTINUATION	-$215,666
2022	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Aging Research	001	3	3/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$164,904
2022	2021	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Aging Research	002	2	9/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = -$50,762

Issue Date FY: 2021 ( Subtotal = $225,907 )
2021	2021	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Aging Research	001	2	6/16/2021	NON-COMPETING CONTINUATION	$0
2021	2021	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Aging Research	000	2	5/13/2021	NON-COMPETING CONTINUATION	$225,907
														Subtotal = $225,907

Issue Date FY: 2020 ( Subtotal = $247,968 )
2020	2020	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Aging Research	000	1	9/9/2020	NEW	$247,968
														Subtotal = $247,968

Grand Total All Awards = $423,068

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Characterization of amyloid-β:α7β2-nicotinic acetylcholine receptor interactions relevant to Alzheimer's disease

Award Number: R21AG067029

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2023

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