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

摘要 阿尔茨海默病（AD）可以被视为一个全身性的问题，虽然最好的特点是作为一种疾病 大脑。人们越来越认识到肠-肝-脑轴对AD的重要性， 肝脏和肠道的功能障碍已显示与AD发病机制相互作用。此外，生物能量转换 在AD中起重要作用。大脑使用葡萄糖作为主要的能量来源 然而，大脑中葡萄糖转运和代谢的减少是糖尿病的早期和持续特征。 AD.在这种能量危机下，肝脏中脂肪酸衍生的酮体可以输入大脑 并用作主要的替代燃料源。因此，AD的发展可能受到整体- 身体脂肪酸代谢，而不是大脑的一个孤立的条件。 这一建议的灵感来自于我们最近的发现，即在胃肠道中发现的脂肪酸亚类的水平降低， 特别是月桂酸，与AD发病机制和认知障碍相关。此外，此前 研究表明椰子油具有神经保护潜力，其中月桂酸占脂肪酸的50%。 酸，对认知和AD相关发病机制的影响。然而，控制AD发病机制及其 与全身脂肪酸代谢的关系尚不明确。 为了至少部分解决这些根本性的差距，我们假设全身代谢 重编程，包括脂肪酸代谢，深刻地参与AD的发展和进展。的 本研究的总体目标（短期目标）是进一步收集人体中的验证和机制数据 受试者，并建立是否3xTg小鼠再现脂肪酸代谢异常沿着肠道- 肝-脑轴，使它们可用于探索机制和测试潜在的治疗方法。在目标1中， 我们将使用多组学方法验证AD中的脂肪酸代谢失调， 样本集我们的工作假设是，轻度认知障碍（MCI）或AD患者的脂肪酸水平降低， 受试者将伴有脂肪酸合成（FAS）下调和/或脂肪酸β- 氧化（FAO），局部在人脑中。在目标2中，我们将确定AD相关的全身脂肪酸 代谢和是否靶向它可以干预AD使用小鼠模型。我们的假设是 脂肪酸代谢失调将沿着肠-肝-脑轴存在， 通过补充月桂酸可以延缓和/或减轻AD的发病。 预期的结果包括我们以前在人体组织中的工作的验证和额外的增益。 深入了解AD全身脂肪酸失调的机制。重要的是，我们将提供 确定脂肪酸补充剂是否会影响AD相关结局的临床前证据。 这项多学科研究的成功实施将为今后的发展奠定基础， 使用月桂酸或其它脂肪酸干预人类受试者的AD病理学的新范例。

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.