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.

项目摘要/摘要 阿尔茨海默氏病（AD）是一种由多种病理生理过程开发的复杂疾病 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 通过饮食和多不饱和脂肪酸（PUFA）摄入量可以改变酸，似乎会影响进展 在AD中，该提案的总体目标是开发一种特定的N-6 PUFA docosapentaenoic Acid（DPAN-6） 有希望的新脂质调节剂，作用于AD中的多个靶标。我们假设DPAN-6调节TGFβ 以及用于改善免疫细胞功能和胰岛素耐药性的绝缘/IGF信号传导途径 病理和保护神经元的认知。 DPAN-6源自N-6前体亚油酸。我们的理由 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 减少了Aß斑块，神经炎症，小胶质细胞增多，星形胶质细胞增多和凋亡。另外，它增加了Aβ 自身抗体，神经生长因子，BDNF和NPTX2，改善了旧E4FAD小鼠的认知缺陷。高的 亚油酸饮食抑制CD4+ T细胞脑侵入和环氧合酶-2（COX2），这是非甾体类靶标 抗炎药（NSAIDS）。最近，新兴研究报告说，较低的摄入n-6亚油酸是 与AD或轻度认知障碍患者老龄化患者认知能力下降的风险有关。但是， 潜在的治疗靶标和机制尚不清楚。 该建议还将填补N-6 PUFA对AD的影响的知识差距。 N-6 Pufas还没有 在广告中得到了充分研究。 N-6花生四烯酸（ARA）是用于产生Cox1和Cox2的底物 前列腺素，炎症的重要介质。这是我们在此提案中追求的两个具体目标 使用EFAD和APOE-TR AD小鼠。 AIM 1是确定DPAN-6是否调节TGFβ /SMAD信号传导 提高免疫力并治疗AD神经病理学“阳性”和“阴性”病变的途径，从而改善 APOE广告模型中的认知缺陷。 AIM 2是确定DPAN-6在还原中的神经保护作用 通过调节胰岛素/胰岛素样生长因子I（IGF-I）信号通路，胰岛素抵抗。我们也会 研究旧EFAD小鼠中DPAN-6与N-3 DHA的结合的协同作用。 该建议具有创新性和意义，因为它基于DPAN-6调节的初始证据 TGFβ和胰岛素/IGF信号传导途径增强治疗AD病理的免疫力，保护神经元 并改善旧E4FAD小鼠的认知定义。如果实现我们的目标，我们将发展DPAN-6作为小说 脂质调节剂用于处理广告的脂质调节剂，可以容易移至临床试验，因为它是安全的，潜在的，并且可以是 被大脑吸收。那是DPAN-6是广告干预的强大但出乎意料的新候选人。我们也会 阐明了流行病学中亚油酸的受保护机制，其中LA效应由其解释 代谢物DPAN-6。