Modulation of TGF-beta signaling by omega-6 polyunsaturated fatty acids for treating AlzheimerâÂÂs disease

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种由多种病理生理过程发展而来的复杂疾病， 衰老，包括免疫功能和脂质代谢失调。因为免疫细胞和脑脂肪 多不饱和脂肪酸（PUFA）的摄入似乎会影响进展， 本提案的总体目标是开发一种特定的n-6 PUFA二十二碳五烯酸（DPAn-6）， 一种有前途的新型脂质调节剂，作用于AD中的多个靶点。我们假设DPAn-6调节TGFβ 和胰岛素/IGF信号通路，以改善免疫细胞功能和胰岛素抵抗，用于治疗AD 病理和保护神经元认知。DPAn-6衍生自n-6前体亚油酸。我们的理据 是基于我们广泛的初步数据，流行病学和临床研究。我们发现口服DPAn-6 减少斑块、神经炎症、小胶质细胞增生、星形胶质细胞增生和细胞凋亡。此外，它还增加了Aβ 自身抗体，神经生长因子，BDNF和NPTX 2，改善老年E4 FAD小鼠的认知缺陷。高 亚油酸饮食抑制CD 4 + T细胞脑侵袭和非甾体类药物的靶点环氧合酶2（COX 2）， 抗炎药（NSAIDs）。最近，新的研究报告说，较低的摄入量n-6亚油酸是 与AD或轻度认知障碍老年患者认知功能下降的风险相关。但 潜在的治疗靶点和机制是未知的。 该提案还将填补n-6 PUFA对AD影响的知识空白。n-6 PUFA没有 在AD中得到了很好的研究。N-6花生四烯酸（ARA）是COX 1和COX 2的底物， 重要的炎症介质--洋地黄素。因此，我们在这项建议中追求两个具体目标 使用EFAD和APOE-TR AD小鼠。目的1是确定DPAn-6是否调节TGFβ /Smad信号转导 途径，以提高免疫力和治疗AD神经病理学“阳性”和“阴性”病变，从而改善 APOE AD模型中的认知缺陷。目的2是确定DPAn-6在降低脑缺血再灌注损伤中的神经保护作用。 胰岛素抵抗是通过调节胰岛素/胰岛素样生长因子I（IGF-I）信号通路来实现的。我们还将 研究DPAn-6与n-3 DHA组合在老年EFAD小鼠中的协同作用。 这一建议是创新和重要的，因为它是基于初步证据，DPAn-6调节 TGFβ和胰岛素/IGF信号通路，以增强免疫力，治疗AD病理，保护神经元 并改善老年E4 FAD小鼠的认知缺陷。如果我们的目标实现，我们将开发DPAn-6作为一种新的 用于治疗AD的脂质调节剂，由于其安全、有效， 被大脑占据。因此，DPAn-6是一种强有力但尚未开发的AD干预新候选药物。我们还将 阐明亚油酸在流行病学中的保护机制，其中LA效应由其 代谢产物DPAn-6。

Project Summary/Abstract Alzheimer’s disease (AD) is a complex disease developed from multiple pathophysiologic processes with aging, including the dysregulation of immune function and lipid metabolism. Since immune cells and brain fatty acids are modifiable through diet and polyunsaturated fatty acid (PUFA) intake appears to affect the progression of AD, the overall goal of this proposal is to develop one specific n-6 PUFA docosapentaenoic acid (DPAn-6) as a promising new lipid modulator acting on multiple targets in AD. We hypothesize that DPAn-6 modulates TGFβ and insuling/IGF signaling pathway to improve immune cellular function and insulin resistance for treating AD pathologies and protecting neurons cognition. DPAn-6 is derived from n-6 precursor linoleic acid. Our rationale is based on our extensive preliminary data, epidemiological and clinical studies. we found that oral DPAn-6 reduced Aß plaques, neuroinflammation, microgliosis, astrogliosis and apoptosis. In addition, it increases Aβ autoantibodies, nerve growth factor, BDNF and NPTX2, improving cognitive deficits in old E4FAD mice. High linoleic acid diet inhibited CD4+ T cell brain invasion and cyclooxygenase-2 (COX2), the target of nonsteroidal anti-inflammatory drugs (NSAIDs). Recently, emerging studies report that lower intake n-6 linoleic acid is associated with risk of cognitive decline in aging patients with AD or mild cognitive impairment. However, the underlying therapeutic targets and mechanisms are unknown. This proposal will also fill in a knowledge gap of the impact of n-6 PUFAs on AD. n-6 PUFAs have not been well-studied in AD. N-6 arachidonic acid (ARA) is a substrate for COX1 and COX2 that produces prostaglandins, the important mediators for inflammation. Thus, we pursue two specific aims in this proposal using EFAD and APOE-TR AD mice. Aim 1 is to determine whether DPAn-6 modulates TGFβ /Smad signaling pathway to boost immunity and treat AD neuropathological “positive” and “negative” lesions, and thus improving cognitive deficits in APOE AD models. Aim 2 is to determine the neuroprotective role of DPAn-6 in reducing insulin resistance by modulating insulin/insulin-like growth factor I (IGF-I) signaling pathway. We will also investigate a synergistic effect of a combination of DPAn-6 with n-3 DHA in old EFAD mice. This proposal is innovative and significant because it is based on initial evidence that DPAn-6 modulates TGFβ and insulin/IGF signaling pathways to enhance immunity for treating AD pathologies, protecting neurons and improving cognitive deficits in old E4FAD mice. If our aims are achieved, we will develop DPAn-6 as a novel lipid modulator for treating AD that can be readily moved to a clinical trial since it is safe, potent, and can be taken up by brain. Thus, DPAn-6 is a strong but unexplored new candidate for AD intervention. We will also elucidate the protective mechanisms of linoleic acid in epidemiology, in which the LA effect is explained by its metabolite DPAn-6.