Modulation of TGF-beta signaling by omega-6 polyunsaturated fatty acids for treating Alzheimer's disease

通过 omega-6 多不饱和脂肪酸调节 TGF-β 信号传导治疗阿尔茨海默病

• 批准号: 10055747
• 负责人: Qiulan Ma
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055747
• 关键词: Active Immunization; Adult; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Apoptosis; Arachidonic Acids; Attenuated; Autoantibodies; Brain; Brain-Derived Neurotrophic Factor; CD4 Positive T Lymphocytes; Cell physiology; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive deficits; Complex; Data; Deposition; Diet; Disease; Docosahexaenoic Acid n-3; Docosahexaenoic Acids; Elderly; Epidemiology; Experimental Designs; Fatty Acids; Functional disorder; Gene Expression; Genes; Genetic Risk; Goals; Homeostasis; Human; IGF1 gene; IGF2 gene; Immune; Immune Tolerance; Immunity; Impaired cognition; Inflammation; Inflammation Mediators; Inflammatory; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intake; Intervention; Knowledge; Lesion; Linoleic Acids; Lipids; Memory; Microglia; Mus; Natural Increases; Natural Products; Nerve Growth Factors; Neurons; Non-Steroidal Anti-Inflammatory Agents; Omega-6 Fatty Acids; Oral; Outcome; PTGS1 gene; Passive Immunization; Pathogenicity; Pathology; Patients; Plasma; Polyunsaturated Fatty Acids; Preventive; Process; Property; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Public Health; Receptor Gene; Reducing diet; Reporting; Resistance; Risk; Role; Senile Plaques; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Transforming Growth Factor beta; abeta oligomer; aged; astrogliosis; base; brain cell; cognitive function; cooperative study; cyclooxygenase 2; docosapentaenoic acid; effective intervention; epidemiology study; immune function; immunoregulation; improved; in vivo; innovation; lipid metabolism; mRNA Expression; mild cognitive impairment; mouse model; neuroinflammation; neuroprotection; neurotoxic; novel; therapeutic target; treatment effect; young adult

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.

项目概要/摘要 阿尔茨海默病（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的失调。由于免疫细胞和脑脂肪 酸可以通过饮食改变，多不饱和脂肪酸 (PUFA) 的摄入量似乎会影响进展 AD 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) 作为 一种有前途的新型脂质调节剂，作用于 AD 的多个靶点。我们假设 DPAn-6 调节 TGFβ 和胰岛素/IGF信号通路改善免疫细胞功能和胰岛素抵抗以治疗AD 病理学和保护神经元认知。 DPAn-6 衍生自 n-6 前体亚油酸。我们的理由 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 Aß 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，它还能增加 Aβ 自身抗体、神经生长因子、BDNF 和 NPTX2，改善老年 E4FAD 小鼠的认知缺陷。高的 亚油酸饮食抑制 CD4+ T 细胞脑侵袭和非甾体类药物靶点环氧合酶 2 (COX2) 抗炎药（NSAID）。最近，新兴研究报告称，较低的 n-6 亚油酸摄入量 与患有 AD 或轻度认知障碍的老年患者认知能力下降的风险相关。然而， 潜在的治疗靶点和机制尚不清楚。 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 COX1 和 COX2 的底物，可产生 前列腺素，炎症的重要介质。因此，我们在此提案中追求两个具体目标 使用 EFAD 和 APOE-TR AD 小鼠。目标 1 是确定 DPAn-6 是否调节 TGFβ /Smad 信号传导 途径增强免疫力并治疗 AD 神经病理“阳性”和“阴性”病变，从而改善 APOE AD 模型中的认知缺陷。目标 2 是确定 DPAn-6 在减少 通过调节胰岛素/胰岛素样生长因子 I (IGF-I) 信号通路来抵抗胰岛素。我们还将 研究 DPAn-6 与 n-3 DHA 组合对老年 EFAD 小鼠的协同作用。 该提案具有创新性且意义重大，因为它基于 DPAn-6 调节的初步证据 TGFβ 和胰岛素/IGF 信号通路增强免疫力，治疗 AD 病理，保护神经元 并改善老年 E4FAD 小鼠的认知缺陷。如果我们的目标实现，我们将开发 DPAn-6 作为小说 用于治疗 AD 的脂质调节剂，可以很容易地进入临床试验，因为它安全、有效，并且可以 被大脑吸收。因此，DPAn-6 是一种强大但未经探索的 AD 干预新候选者。我们还将 阐明亚油酸在流行病学中的保护机制，其中 LA 效应是通过其 代谢物 DPAn-6。