Wednesday, December 31, 2025 12/31/2025

Reversing Microglial Inflammarafts and Mitochondrial Dysfunction in Alzheimer's Disease

Award Number: R01AG081037
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Reversing Microglial Inflammarafts and Mitochondrial Dysfunction in Alzheimer's Disease - Project Summary Neuroinflammation is a major factor in the progression of Alzheimer's disease (AD). Inflammatory brain microglia are characterized by altered cholesterol and lipid metabolism. Cholesterol and many receptors governing inflammatory responses colocalize in the ordered membrane microdomains often designated as lipid rafts. Upon activation, lipid raft resident and recruited molecules assemble and initiate signaling cascades leading to inflammation. We have identified the apoA-I binding protein (AIBP, encoded by the APOA1BP gene) as a key regulator of cellular cholesterol metabolism, which can selectively target lipid rafts in inflammatory cells (inflammarafts) via its binding to TLR4. While extracellular AIBP regulates cholesterol depletion from the plasma membrane and controls lipid rafts, intracellular AIBP localizes to mitochondria, facilitates mitophagy and helps maintain normal mitochondrial function and control oxidative stress. Apoa1bp-/- APP/PS1 mice present more amyloid beta (Aβ) plaques, an exacerbated dysfunctional microglia phenotype and show increases in cell death when compared to APP/PS1 mice. Mitochondria in AIBP-deficient microglia are morphologically distorted, with a characteristic hyper-branched and cupped shape, typically seen following oxidative stress. The AAV-mediated expression of a secreted form of AIBP in the brain of Apoa1bp-/- APP/PS1 mice restored the homeostatic microglia morphology. The goal of this proposal is to delineate mechanisms governing protective effects of AIBP in the AD brain, focusing on microglial lipid rafts and on mitochondrial dysfunction. Specifically, in Aim 1 we propose to test the hypothesis that extracellular AIBP reverses pathological lipid rafts in microglia to reduce neuroinflammation and protect against neurodegeneration in a mouse model of AD. We have identified a TLR4- binding domain in the AIBP molecule and demonstrated that an AIBP(ΔTLR4) variant, which does not bind TLR4, cannot reverse lipid raft alterations. Using AAV delivery, we plan to restore expression of secreted variants of AIBP in the brain of Apoa1bp-/- APP/PS1 mice and expect that AIBP(wt) but not AIBP(ΔTLR4) will lessen neuroinflammation, the Aβ plaque burden and accumulation of phospho-tau. We also expect improvements in memory and learning. In Aim 2, we will be testing the hypothesis that intracellular AIBP protects mitochondrial dynamics and function in a mouse model of AD. Mitochondria are the major sites displaying concentration of intracellular AIBP, and preliminary studies suggest AIBP involvement in control of mitochondrial function, mitophagy and oxidative stress. Methods will include correlated light microscopy and 3D EM across scales, leveraging advances in serial blockface scanning EM and EM tomography, along with correlated measures of bioenergetics by Seahorse. To test relevance of the proposed mechanisms to human AD, in Aim 3 we will characterize AIBP-related markers of lipid rafts and mitochondrial dysfunction in postmortem and biopsy brain sections from AD subjects.


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: 2026 ( Subtotal = $690,400 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	4	12/10/2025	NON-COMPETING CONTINUATION	$690,400
														Subtotal = $690,400

Issue Date FY: 2025 ( Subtotal = $753,317 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	3	11/21/2024	NON-COMPETING CONTINUATION	$691,822
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	3	7/15/2025	NON-COMPETING CONTINUATION	$61,495
														Subtotal = $753,317

Issue Date FY: 2024 ( Subtotal = $781,587 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	2	5/20/2024	NON-COMPETING CONTINUATION	$78,159
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	2	12/7/2023	NON-COMPETING CONTINUATION	$703,428
														Subtotal = $781,587

Issue Date FY: 2023 ( Subtotal = $789,121 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	1	11/23/2022	NEW	$789,121
														Subtotal = $789,121

Grand Total All Awards = $3,014,425

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Reversing Microglial Inflammarafts and Mitochondrial Dysfunction in Alzheimer's Disease

Award Number: R01AG081037

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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