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Contribution of DNA Repair Deficits to Alzheimer Pathogenesis

Award Number: RF1AG053981
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2021

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Contribution of DNA Repair Deficits to Alzheimer Pathogenesis - The increased life expectancy of populations around the world has led to a striking increase in the prevalence of Alzheimer's disease (AD), the most common and costly among neurodegenerative disease. It has become increasingly evident that DNA damage is exacerbated in neurons of AD patients, which may lead to neuronal dysfunction and contribute to disease development and progression. In recent studies, we demonstrated an increase in DNA double-strand breaks (DSBs), the most severe form of DNA damage, in neurons of human amyloid precursor protein (hAPP) transgenic mice, which simulate several aspects of AD. Interestingly, we also discovered that hAPP mice showed a delay in the repair of activity-induced DSBs, when compared to wildtype mice, suggesting deficits in their neuronal DNA repair machinery. We subsequently discovered that breast cancer factor 1 (BRCA1), a well-described DSB repair factor and tumor suppressor, was depleted by approximately 50% in brains of hAPP mice and of patients with AD. Reducing BRCA1 levels in the dentate gyrus of wildtype mice to a similar extent by lentiviral expression of anti-BRCA1 shRNA increased the number of neuronal DSBs in this region and led to cognitive impairments. It is also possible that alterations in other DSB repair factors contribute to AD pathogenesis also. We hypothesize that efficient repair of DSBs is essential for proper neuronal function. We further hypothesize that deficits in neuronal DSB repair critically contribute to the accumulation of neuronal DNA damage in AD and that this process contributes to morphological and functional neuronal alterations that underlie the inexorable cognitive decline this disease causes. To test these hypotheses, we will determine which DSB repair factors are altered in postmortem MCI/AD tissue, examine the pathogenic mechanisms by which DSB repair factors are altered, investigate how DSB repair factors are regulated in neurons, and test whether elevating BRCA1 levels is of therapeutic benefit in AD-related models. Protecting the neuronal genome by increasing DNA repair is a novel strategy that might help prevent or slow the progression of AD and related disorders.


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: 2022 ( Subtotal = $0 )
2022	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	1	2/23/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	001	1	3/11/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	1	3/11/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	001	1	12/10/2019	SUPPLEMENT FOR EXPANSION	$0
2020	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	1	12/10/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $186,249 )
2017	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	1	8/31/2017	SUPPLEMENT FOR EXPANSION	$186,249
														Subtotal = $186,249

Issue Date FY: 2016 ( Subtotal = $3,714,865 )
2016	2016	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Aging Research	000	1	7/21/2016	NEW	$3,714,865
2016	2016	J DAVID GLADSTONE INSTITUTES	POST OFFICE BOX 419100	SAN FRANCISCO	CA	941419100	SAN FRANCISCO	USA	Aging Research	001	1	7/26/2016	NEW	$0
														Subtotal = $3,714,865

Grand Total All Awards = $3,901,114

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Contribution of DNA Repair Deficits to Alzheimer Pathogenesis

Award Number: RF1AG053981

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2021

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