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Mitochondrial calcium uptake in Alzheimer’s disease

Award Number: R00AG065445
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Mitochondrial calcium uptake in Alzheimer’s disease - Abstract: Alzheimer's disease (AD) is characterized by the loss of memory accompanied by neuronal cell death and metabolic dysfunction. Numerous studies have reported a dysregulation in neuronal intracellular calcium (1Ca2+) signaling as an early event in AD pathogenesis. It is thought that a prolonged elevation in neuronal 1Ca2+ promotes excessive mitochondrial calcium (mCa2+) uptake, yet to date no study has examined the contribution of mCa2+ uptake to disease progression. Since mCa2+ flux is an important regulator of cellular respiration and cell death, both of which are involved in AD pathogenesis, we hypothesize that mCa2+ overload is a key contributor to AD pathology and may contribute to metabolic deficits and neuronal demise. To define the role of mCa2+ exchange in AD we have generated 3xTg-AD mutant mice with neuronal-specific deletion of Mitochondrial Calcium Uniporter (MCU), which is required for mCa2+ uptake. In addition, we have generated a gain-of-function mutant mouse expressing the recently identified mitochondrial calcium uniporter beta subunit (MCUb). MCUb was recently reported as a negative regulator of mCa2+ uptake and we have observed substantial changes in its expression in AD. These models will allow causative experimentation to test if mCa2+ uptake drives AD progression. Mice will be examined for alterations in memory, amyloidosis, tau-pathology, oxidative stress, synaptic and metabolic function. Preliminary data suggest that mCa2+ uptake overload impairs the clearance of misfolded proteins and dysfunctional mitochondria. Therefore, we will mechanistically examine the link between mCa2+ exchange and autophagic and mitophagic pathways. Optimally, the proposed studies will discover new therapeutic targets for AD and associated mitochondrial dysfunction and provide a training and research platform to promote the Pis independent research career.


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	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	5	8/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $242,702 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	5	8/22/2024	NON-COMPETING CONTINUATION	$242,702
														Subtotal = $242,702

Issue Date FY: 2023 ( Subtotal = $430,395 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	002	4	8/24/2023	NON-COMPETING CONTINUATION	$245,883
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	003	4	9/14/2023	SUPPLEMENT FOR EXPANSION	$107,562
2023	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	3	10/27/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
2023	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	001	3	7/24/2023	EXTENSION WITH OR WITHOUT FUNDS	$76,950
														Subtotal = $430,395

Issue Date FY: 2022 ( Subtotal = $249,000 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	3	8/23/2022	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $922,097

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Mitochondrial calcium uptake in Alzheimer’s disease

Award Number: R00AG065445

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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