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Impact of ApoE in Novel Rat Models of Late-Onset AD

Award Number: R21AG085087
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Impact of ApoE in Novel Rat Models of Late-Onset AD - Apolipoprotein E4 (ApoE4) is recognized as a strong risk factor for the development of late-onset Alzheimer’s disease (LOAD). To better understand the impact of ApoE genotype on the emergence and progression of LOAD and to effectively evaluate therapeutic interventions for this condition appropriate experimental animal models are needed. To date, most animal model studies designed to address the contributions of ApoE genotype to AD have largely centered around the use of transgenic mice. Typically, most transgenic lines for AD rely on highly artificial over-expression of transgenes and largely incorporate one or more early-onset FAD mutations in AbPP or presenilin. Moreover, transgenic animals are prone to developmental and insertional effects on the host genome and are susceptible to loss of transgene expression and genetic drift in subsequent generations. In addition to these caveats, another major shortcoming of transgenic lines is that any AD pathology that develops typically is from a ‘sole source’ of transgene expression. In most cases, the ‘sole source’ of transgenic proteins results from strong over-expression in neuronal cells. With regards to AD, it is known that besides neurons neighboring astrocytes and microglia can express AbPP, produce Ab peptides and participate in AD pathogenesis. In addition, vascular cell types including endothelial cells, smooth muscle cells and pericytes all express AbPP, produce Ab peptides and reside at the site of CAA, a common vascular co-morbidity of LOAD. Since the complexity of the cellular origins of Ab in AD are not captured in ‘sole source’ transgenic models they fail to reveal the true pathogenesis of this disorder and an accurate understanding of the impact of ApoE. This glaring shortcoming has prompted the quest to generate better experimental animal models for LOAD that more fully capture the pathogenesis of this condition and more accurately reflect human disease. The overall goal of this exploratory proposal is to study the impact of ApoE genotype on the emergence and progression of LOAD pathologies and cognitive impairment using a novel gene-edited rat model (CrHuAb) used to generate bigenic CrHuAb/hApoE3 and CrHuAb/hApoE4 rats. These novel and timely rats will provide superior, state-of-the-art preclinical models that will more realistically reflect the true pathogenesis of LOAD that develops in patients compared to transgenic mice commonly used in the field.


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 = $236,250 )
2025	2025	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Aging Research	001	2	4/28/2025	NON-COMPETING CONTINUATION	$23,625
2025	2025	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Aging Research	000	2	11/21/2024	NON-COMPETING CONTINUATION	$212,625
														Subtotal = $236,250

Issue Date FY: 2024 ( Subtotal = $196,875 )
2024	2024	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Aging Research	000	1	2/7/2024	NEW	$196,875
														Subtotal = $196,875

Grand Total All Awards = $433,125

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Impact of ApoE in Novel Rat Models of Late-Onset AD

Award Number: R21AG085087

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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