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Targeting Whole Body Fatty Acid Metabolism in Alzheimers Disease, with Special Interest in Lauric Acid

Award Number: R21AG072561
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Targeting Whole Body Fatty Acid Metabolism in Alzheimers Disease, with Special Interest in Lauric Acid - Abstract Alzheimer’s disease (AD) can be viewed as a whole-body problem, although best characterized as a disease of the brain. There has been growing appreciation of the importance of the gut-liver-brain axis to AD, and dysfunctions in the liver and gut have been shown to interact with AD pathogenesis. Further, bioenergetic shifts involving fatty acid metabolism play a significant role in AD. The brain uses glucose as its primary fuel for energy production; however, reduced glucose transport and metabolism in the brain is an early and constant feature of AD. Under this energetic crisis, ketone bodies derived from fatty acids in the liver can be imported into the brain and used as the primary alternate fuel source. Consequently, development of AD may be influenced by whole- body fatty acid metabolism, rather than being an isolated condition of the brain. This proposal is inspired by our recent findings that decreased levels of a subset of fatty acids found in the brain, lauric acid in particular, correlate with AD pathogenesis and cognitive impairment. In addition, previous studies have shown the neuroprotective potential of coconut oil, in which lauric acid makes up ~50% of the fatty acids, on cognition and AD-related pathogenesis. However, mechanisms governing AD pathogenesis and its relationship to whole-body fatty acid metabolism are ill-defined. To at least partially address these fundamental gaps, we hypothesize that whole-body metabolic reprogramming, including fatty acid metabolism, is profoundly involved in AD development and progression. The overall objective of this study (short-term goal) is to further collect validation and mechanistic data in human subjects, and to establish whether 3xTg mice reproduce abnormalities of fatty acid metabolism along the gut- liver-brain axis, making them useful for exploration of mechanisms and testing of potential treatments. In Aim 1, we will validate dysregulated fatty acid metabolism in AD using a multi-omics approach on another independent sample set. Our working hypothesis is that decreased fatty acids levels in mild cognitive impairment (MCI) or AD subjects will be accompanied by down-regulated fatty acid synthesis (FAS) and/or up-regulated fatty acid β- oxidation (FAO), locally in the human brain. In Aim 2, we will determine AD-associated whole-body fatty acid metabolism and whether targeting it can intervene in AD using a mouse model. Our working hypothesis is that dysregulated fatty acid metabolism will exist along the gut-liver-brain axis, and that targeting those alterations through lauric acid supplementation can delay and/or alleviate AD pathogenesis. The expected outcomes include validation of our previous work in human tissues and the gain of additional insights into the mechanisms underlying whole-body fatty acid dysregulation in AD. Importantly, we will provide pre-clinical evidence establishing whether fatty acid supplementation can affect AD-associated outcomes. Successful implementation of this multidisciplinary study will lay the foundation for the future development of novel paradigms using lauric acid or other fatty acids to intervene in AD pathology in human 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: 2024 ( Subtotal = -$74,828 )
2024	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Aging Research	001	2	7/16/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$74,828
2024	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Aging Research	000	2	6/3/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = -$74,828

Issue Date FY: 2023 ( Subtotal = -$1 )
2023	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Aging Research	001	2	5/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	1	2/2/2023	NEW	-$1
														Subtotal = -$1

Issue Date FY: 2022 ( Subtotal = $1 )
2022	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	1	4/4/2022	NEW	-$459,770
2022	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Aging Research	001	2	4/5/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$459,771
														Subtotal = $1

Issue Date FY: 2021 ( Subtotal = $459,771 )
2021	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	1	5/28/2021	NEW	$459,771
														Subtotal = $459,771

Grand Total All Awards = $384,943

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Targeting Whole Body Fatty Acid Metabolism in Alzheimers Disease, with Special Interest in Lauric Acid

Award Number: R21AG072561

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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