Targeting Whole Body Fatty Acid Metabolism in Alzheimers 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问题，尽管最好的特征是一种疾病 大脑的一部分。越来越多的人认识到肠道-肝脏-脑轴对AD的重要性，以及 肝脏和肠道功能障碍已被证明与AD的发病机制相互作用。此外，生物能量的转变 参与脂肪酸代谢在阿尔茨海默病中起着重要作用。大脑使用葡萄糖作为能量的主要燃料。 然而，大脑中葡萄糖运输和新陈代谢减少是早期和持续的特征 广告。在这种能量危机下，从肝脏中的脂肪酸中提取的酮体可以被输入大脑 并用作主要的替代燃料来源。因此，阿尔茨海默病的发展可能受到整体因素的影响。 身体的脂肪酸代谢，而不是孤立的大脑状况。 这一建议的灵感来自于我们最近的发现，即降低在 大脑，尤其是月桂酸，与阿尔茨海默病的发病和认知障碍有关。此外，以前的 研究表明，椰子油具有神经保护作用，其中月桂酸占脂肪的50%左右。 酸类，对认知和AD相关发病机制的影响。然而，阿尔茨海默病的发病机制及其机制 与全身脂肪酸新陈代谢的关系还不清楚。 为了至少部分解决这些根本差距，我们假设全身新陈代谢 重新编程，包括脂肪酸代谢，与阿尔茨海默病的发展和进展密切相关。这个 这项研究的总体目标(短期目标)是进一步收集人类的有效性和机械性数据 受试者，并确定3xTg小鼠是否沿着肠道复制脂肪酸代谢异常- 肝脏-脑轴，使其有助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在另一独立的AD患者身上验证失调的脂肪酸代谢 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 受试者将伴随着下调的脂肪酸合成(FAS)和/或上调的脂肪酸β- 氧化(粮农组织)，在人脑的局部。在目标2中，我们将确定与AD相关的全身脂肪酸 新陈代谢以及靶向它是否可以通过小鼠模型干预AD。我们的工作假设是 肠道-肝脏-脑轴将存在脂肪酸代谢失调，并以这些变化为目标 通过补充月桂酸可以延缓和/或缓解AD的发病。 预期的结果包括验证我们之前在人体组织中的工作，以及获得更多 对阿尔茨海默病全身脂肪酸失调机制的洞察。重要的是，我们将提供 临床前证据表明，补充脂肪酸是否会影响AD相关的预后。 这项多学科研究的成功实施将为未来的发展奠定基础 使用月桂酸或其他脂肪酸干预人类受试者AD病理的新范例。

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.