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Studies of dementia pathogenesis in genetically faithful rat models of Familal Alzheimer disease

Award Number: R01AG063407
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Studies of dementia pathogenesis in genetically faithful rat models of Familal Alzheimer disease - Project Summary/Abstract Alzheimer's Disease (AD) is the most common cause of ageing-dependent dementia in the world and is associated with cerebral amyloid plaques, mostly composed of Aβ peptides. These peptides are produced by a double cleavage of the amyloid precursor protein (APP). BACE1 cleavage produces the C-terminal fragment, β-CTF, which is then processed into several Aβ isoforms by γ-secretase. Genetic data suggest that regulation of APP processing contributes to AD. In addition, a polymorphism of APP that reduces processing of APP by BACE1 protects from sporadic AD and from normal aging-dependent cognitive decline. Thus, the human genetic evidence indicates that APP and APP processing are important for normal cognitive functions. To gain insights into the pathogenic mechanisms of AD we introduced a familial APP mutation (the Swedish K670N/M671L mutation, AppS rats) and a familial PSEN1 mutation (L435F, Psen1LF rats) into the genomic App and Psen1 rat loci, respectively. Rat and human APP differ by 3 amino-acids in the Aβ region: given that aggregated forms of Aβ are considered by most the main pathogenic factor in AD, and given that human Aβ may have higher propensity than rodent Aβ to form yet-to-be-identified toxic forms of Aβ, together with the Swedish mutations we introduced mutations to “humanize” the rat Aβ sequence. As controls, we produced rats carrying only the humanized Aβ sequence (Apph rats). We choose a knock in (KI) approach rather than the more common transgenic overexpression approach because KI models make no preconceived assumption about pathogenic mechanisms, except the unbiased genetic one. In contrast, transgenic models, which produce high levels of Aβ and can readily deposit amyloid plaques, are based on the hypothesis that plaques and/or other forms of toxic Aβ have a central pathogenic role. We propose to dissect pathogenic mechanisms of neurodegeneration using these KI rat models of FAD. We will study the impact of App and Psen1 FAD mutations on APP processing, brain pathology, neuro-inflammation and neurodegeneration, synaptic transmission/plasticity, learning & memory. In addition, we will assess the role of distinct APP-derived metabolites in neurodegenerative processes triggered by mutant APP and PSEN1. These studies will test the mainstream hypotheses but also consider alterative pathogenic mechanisms, including the possibility that FAD pathogenesis may depend on the alteration of the normal function of APP and PSEN1 in the brain.


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	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	000	5	5/5/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	001	5	12/1/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$241,061
2024	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	4	12/1/2023	NON-COMPETING CONTINUATION	-$241,061
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $786,979 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	001	5	2/3/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$786,979
2023	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	4	2/3/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $786,979

Issue Date FY: 2022 ( Subtotal = $786,979 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	4	1/27/2022	NON-COMPETING CONTINUATION	$708,282
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	001	4	6/2/2022	NON-COMPETING CONTINUATION	$78,697
														Subtotal = $786,979

Issue Date FY: 2021 ( Subtotal = $786,979 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	3	1/29/2021	NON-COMPETING CONTINUATION	$786,979
														Subtotal = $786,979

Issue Date FY: 2020 ( Subtotal = $786,979 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	2	3/16/2020	NON-COMPETING CONTINUATION	$786,979
														Subtotal = $786,979

Issue Date FY: 2019 ( Subtotal = $786,979 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	1	3/23/2019	NEW	$786,979
														Subtotal = $786,979

Grand Total All Awards = $3,934,895

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Studies of dementia pathogenesis in genetically faithful rat models of Familal Alzheimer disease

Award Number: R01AG063407

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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