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

项目摘要/摘要 阿尔茨海默病(AD)是一种复杂的疾病，由多种病理生理过程发展而来 衰老，包括免疫功能和脂类代谢的失调。因为免疫细胞和脑脂肪 酸是可以通过饮食改变的，多不饱和脂肪酸(PUFA)的摄入似乎会影响病情的进展 对于AD，本提案的总体目标是开发一种特定的n-6多不饱和脂肪酸(DPAn-6)作为 一种有希望的新的作用于AD多靶点的脂质调节剂。我们推测DPAn-6调控转化生长因子β 胰岛素/胰岛素样生长因子信号通路改善免疫细胞功能和胰岛素抵抗治疗AD 病理学和保护神经元认知。DPAn-6由n-6前体亚油酸衍生而来。我们的理论基础 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Aü斑块、神经炎症、小胶质细胞增多症、星形胶质细胞增多症和细胞凋亡。此外，它还增加了Aβ 自身抗体、神经生长因子、脑源性神经营养因子和NPTX2，改善老年E4FAD小鼠的认知缺陷。高 亚油酸饮食抑制非甾体激素靶标环氧合酶-2(COX2)和CD4+T细胞脑侵袭 抗炎药(NSAIDs)。最近，新出现的研究报告称，较低的n-6亚油酸摄入量 与老年AD患者或轻度认知障碍患者认知功能下降的风险有关。然而， 潜在的治疗靶点和机制尚不清楚。 该提案还将填补关于n-6种多不饱和脂肪酸对AD影响的知识空白。N-6个多不饱和脂肪酸没有 在公元前就学得很好了。N-6花生四烯酸(ARA)是COX1和COX2的底物，产生 前列腺素，炎症的重要介质。因此，我们在这项建议中追求两个具体目标 用EFAD和APOE-TRAD小鼠。目的1是确定DPAn-6是否调节转化生长因子β/Smad信号 提高免疫力和治疗AD神经病理“阳性”和“阴性”病变的途径，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 通过调节胰岛素/胰岛素样生长因子-I(IGF-I)信号通路发生胰岛素抵抗。我们还将 研究DPAn-6和n-3DHA在老年EFAD小鼠中的协同作用。 这一建议具有创新性和重要意义，因为它是基于DPAn-6调制的初步证据 转化生长因子β和胰岛素/胰岛素样生长因子信号通路增强免疫力治疗AD病理，保护神经元 改善老年E4FAD小鼠的认知缺陷。如果我们的目标实现，我们将把DPAn-6作为一种小说来开发 用于治疗阿尔茨海默病的脂质调节剂，由于它是安全、有效和可以 被大脑吸收。因此，DPAn-6是一种强有力但尚未探索的AD干预新候选基因。我们还将 在流行病学中阐明亚油酸的保护机制，其中LA效应是通过其 代谢物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.