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Assessing the role of APOE in glial lipid droplet metabolism and function

Award Number: R01AG081421
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Assessing the role of APOE in glial lipid droplet metabolism and function - ABSTRACT Alzheimer’s disease (AD) is one of the predominant causes of disability and dependency among older people, and the sixth leading cause of death in the United States. Late-onset AD is the most common form, with more than 99% of AD cases occurring after age 65. The strongest genetic risk factor for developing late-onset AD is carrying the APOE4 allele. Apolipoprotein E (APOE) is primarily expressed by glial cells in the brain and is the major protein component of lipoprotein particles secreted by astrocytes and microglia. Lipoprotein particles provide a bidirectional mechanism of lipid transport between glia and neurons. Many recent studies suggest that a disequilibrium in nervous system lipids is associated with increased risk of developing AD. However, the mechanisms by which APOE4 affects cellular lipid homeostasis are incompletely understood. We recently discovered that in glia, APOE can traffic to cytoplasmic lipid droplets (LDs) rather than undergoing secretion on lipoprotein particles. We hypothesize that APOE plays previously unrecognized roles in cellular lipid metabolism by acting directly on LDs in astrocytes and microglia. Astrocytes play important roles in metabolizing peroxidated lipids, while microglia are the primary innate immune effector cells of the central nervous system. In Aim 1, we will test the effect of modulating APOE in astrocytes on cellular lipid composition, metabolism, and lipid peroxidation. In Aim 2, we will test the effect of modulating APOE in microglia on cellular lipid composition, metabolism, and inflammation. In Aim 3, we will fill a key knowledge gap by developing a community resource visualizing and quantifying LDs in various brain regions and cell types in mice of different genotypes and ages. Together, these studies will lead to new insights about the cellular and molecular mechanism by which expression of APOE4 leads to increased risk of late-onset AD. This work could also lead to the identification of novel drug targets for preventing and treating AD.


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 = $560,263 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	000	3	3/25/2025	NON-COMPETING CONTINUATION	$514,527
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	002	3	6/18/2025	NON-COMPETING CONTINUATION	$45,736
2025	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	001	2	5/5/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $560,263

Issue Date FY: 2024 ( Subtotal = $661,171 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	004	2	6/14/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	005	2	8/30/2024	SUPPLEMENT FOR EXPANSION	$6,791
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	001	2	3/19/2024	NON-COMPETING CONTINUATION	$514,527
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	002	2	3/21/2024	SUPPLEMENT FOR EXPANSION	$61,113
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	003	2	6/13/2024	NON-COMPETING CONTINUATION	$57,168
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	000	1	11/30/2023	SUPPLEMENT FOR EXPANSION	$21,572
														Subtotal = $661,171

Issue Date FY: 2023 ( Subtotal = $585,570 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	000	1	5/4/2023	NEW	$585,570
														Subtotal = $585,570

Grand Total All Awards = $1,807,004

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Assessing the role of APOE in glial lipid droplet metabolism and function

Award Number: R01AG081421

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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