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Cardiolipin Remodeling in Alzheimer’s Disease

Award Number: R01AG081422
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: 04/30/2028

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Cardiolipin Remodeling in Alzheimer’s Disease - Aging causes bioenergetic dysfunction in the brain, which is implicated in the pathogenesis of Alzheimer’s disease (AD). Cardiolipin (CL) is a mitochondrial signature phospholipid that is essential for membrane structure, bioenergetics, and signaling pathways. Alterations in brain CL content and acyl compositions are implicated in the pathogenesis of neurodegenerative diseases, including AD and Parkinson’s disease (PD), but the underlying causes of these defects remain elusive. Here, we propose to investigate a novel metabolic pathway by which pathological remodeling of CL promotes the development of AD. This pathway is mediated by the ALCAT1 enzyme, the first acyl-CoA dependent lysocardiolipin acyltransferase previously identified by us. Our pioneering work in the field has identified ALCAT1 as a key mediator of mitochondrial dysfunction in age-related metabolic diseases. We show that upregulation of ALCAT1 expression by reactive oxygen species (ROS) generated by aging promotes mitochondrial dysfunction by catalyzing pathological remodeling of CL with long chain polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). Enrichment of DHA renders CL highly sensitive to oxidative damage by ROS, leading to CL peroxidation and mitochondrial dysfunction. We further show that ablation or pharmacological inhibition of ALCAT1 successfully mitigates various age-related metabolic diseases. Remarkably, our preliminary studies also identified a critical role of ALCAT1 in linking aging to the development of AD, which is supported by our findings that: 1) ALCAT1 deficiency significantly extends lifespan in mice; 2) Ablation of ALCAT1 restores cognitive function and mitigates Aβ plague formation in a mouse model of AD; and 3) ALCAT1 deficiency attenuates neuroinflammation in response to Aβ protein aggregation. These exciting findings lead us to test the hypothesis that CL remodeling by ALCAT1 links aging to the development of AD by promoting mitochondrial dysfunction (Fig.1), which will be tested by three Specific Aims: AIM 1 will determine whether CL remodeling by ALCAT1 links mitochondrial dysfunction to AD; AIM 2 will identify mechanisms by which ALCAT1 promotes neuroinflammation in AD, and AIM 3 will provide proof-of-concept studies in targeting ALCAT1 for the treatment of 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 = $332,281 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Aging Research	001	3	6/13/2025	NON-COMPETING CONTINUATION	$27,125
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Aging Research	000	3	4/8/2025	NON-COMPETING CONTINUATION	$305,156
														Subtotal = $332,281

Issue Date FY: 2024 ( Subtotal = $339,063 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Aging Research	000	2	4/17/2024	NON-COMPETING CONTINUATION	$339,063
														Subtotal = $339,063

Issue Date FY: 2023 ( Subtotal = $339,063 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Aging Research	000	1	5/10/2023	NEW	$339,063
														Subtotal = $339,063

Grand Total All Awards = $1,010,407

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Cardiolipin Remodeling in Alzheimer’s Disease

Award Number: R01AG081422

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: 04/30/2028

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