Targeting Whole-body Fatty Acid Metabolism in Alzheimer’s Disease, with Special Interest in Lauric acid

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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.