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Proteomic and functional analysis of missense variants of APOE associated with Alzheimer disease risk

Award Number: F30AG079580
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Proteomic and functional analysis of missense variants of APOE associated with Alzheimer disease risk - PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia in the United States. Variants in the apolipoprotein E gene (APOE) is strongly associated with development of AD. In the brain, APOE is mostly synthesized in the astrocytes. The primary role of APOE is to deliver lipids and cholesterol from astrocytes to other cell types. Most humans have one of the major allele of APOE, APOE ε2 (R176C), APOE ε3 (reference allele), and APOE ε4 (C130R). These missense variants are associated with different levels of Alzheimer disease risks where APOE ε4 increases the risk of disease whereas APOE ε2 decrease risk of AD. A recent analysis that genotyped over 100,000 patients showed that rare missense variants were associated with different levels of Alzheimer disease risk. The molecular mechanism of how variants in APOE changes astrocyte physiology that could lead to Alzheimer disease is not well known. To attempt to understand this, our previous work adapted mass spectrometry-based thermal proteome profiling to determine changes in protein interaction as a result of missense variants. Using yeast as simplified model, we were able to show mutant thermal proteome profiling to resolve subcomplex level protein-protein interaction disruptions of a protein complexes due to missense variants. To study the role of these rare missense variants on APOE in astrocytes, we will employ an mouse primary astrocyte culture that will generate human APOE with the specific missense variant. First, we will determine the effect of the rare missense variants on the lipoprotein functions and astrocyte physiology. We will determine the differences between the APOE variants of uptake of Aβ peptides, lipidation status, and the effects on the astrocyte transcriptome. Second, we will determine the changes in protein interactions as a result in APOE variants using mutant thermal proteome profiling to detect thermal stability changes. Taken together, these data will expand our understanding of how missense variants change the functions of APOE and help give insight into the molecular mechanisms that result in Alzheimer disease.


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 = $35,370 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	4	7/29/2025	NON-COMPETING CONTINUATION	$35,370
														Subtotal = $35,370

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	3	8/27/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $31,964 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	002	2	8/3/2023	NON-COMPETING CONTINUATION	$31,964
2023	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	001	1	10/25/2022	NEW	$0
2023	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	1	10/21/2022	NEW	$0
														Subtotal = $31,964

Issue Date FY: 2022 ( Subtotal = $37,449 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	1	7/26/2022	NEW	$37,449
														Subtotal = $37,449

Grand Total All Awards = $158,757

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Proteomic and functional analysis of missense variants of APOE associated with Alzheimer disease risk

Award Number: F30AG079580

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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