Can Omega 3 fatty acids Slow Alzheimer Pathogenesis?

Omega 3 脂肪酸可以减缓阿尔茨海默病的发病机制吗？

• 批准号: 7280738
• 负责人: GREGORY M COLE
• 金额: $ 27.07万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7280738
• 关键词: Acids; Actin-Binding Protein; Actins; Adipose tissue; Algae; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Amyloid; Amyloid Proteins; Amyloid deposition; Antioxidants; Apolipoprotein E; Apoptotic; BAD gene; Bad protein; Behavior; Binding Proteins; Biological Assay; Blood Platelets; Brain; Cardiovascular Diseases; Caspase; Cholesterol; Cleaved cell; Cognitive; Cognitive deficits; Complex; Consumption; Curcumin; DLG4 gene; Data; Dendritic Spines; Deposition; Diet; Docosahexaenoic Acids; Early Intervention; Elevation; End Point; Endopeptidases; Family; Fatty Acids; Fatty acid glycerol esters; Fish Oils; Fishes; Gene Expression Regulation; Hippocampus (Brain); Insulinase; Intervention; Linoleic Acids; Lipids; Lipoxygenase; Marines; Measures; Membrane; Membrane Fluidity; Memory; Mercury; Messenger RNA; Modeling; Mus; Muscle; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Non-Steroidal Anti-Inflammatory Agents; Oils; Omega-3 Fatty Acids; Pathogenesis; Pathology; Pathway interactions; Peptide Hydrolases; Peroxisome Proliferator-Activated Receptors; Phosphatidylserines; Phospholipids; Phosphoproteins; Phosphotransferases; Plant Sources; Prealbumin; Prevention; Proteins; Regulation; Research Personnel; Risk; Rodent Model; Safflower Oil; Signal Pathway; Signal Transduction; Slice; Standards of Weights and Measures; Supplementation; Synapses; Synaptophysin; Testing; Tg2576; Time; Tissues; Toxin; Transgenes; Transgenic Mice; Transgenic Organisms; Turmeric extract; Vitamin Deficiency; Vitamins; Weaning; Work; aged; alpha-Linolenic Acid; amyloid pathology; amyloid precursor protein processing; base; cofilin; menhaden; morris water maze; neuron loss; neuroprotection; oxidation; peroxidation; postsynaptic; presynaptic density protein 95; programs; protective effect; response; secretase; social; soy; tau Proteins; tau-protein kinase; treatment trial; vesicle-associated membrane protein

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) risk is reduced by fish consumption, possibly due to long chain omega 3 fatty acids (eicospentaenoic acid (EPA) and docosahexaenoic acid (DHA). Lab chows typically contain abundant soy and fish and are omega-3 fatty acids sufficient raising the issue of whether omega 3 in the chow influences AD pathogenesis in lab models. Aged APPsw AD model mice were placed on a DHA-depleting "Bad" diet with safflower oil as the principal fat. With no evidence for neuron or synaptophysin loss, DHA depletion increased oxidative damage, caspase-cleaved actin and deficits in PSD-95 and the dendritic spine actin-binding protein, drebrin. The effect was transgene-dependent, suggesting that the "Bad" diet is permissive for a selective APP transgene-induced post-synaptic deficit. Only Tg(+) mice on "Bad" diet developed major deficits in mRNA and protein associated with postsynaptic function and memory, including neuroprotective principal investigator3K p85 that regulates both caspase and tau kinase activation. Whether dietary DHA's neuroprotective effects come from regulation of phosphatidylserine levels and principal investigator3-K or from lipoxygenase derived DHA metabolites (neuroprotectin Dl) remains unknown. Amyloid pathology was also reduced by DHA supplementation, but the mechanisms involved also remain unclear: DHA did not induce transthyretin (TTR), an anti-amyloid protein that reduces AD pathology and has been reportedly induced by fish oil. Currently fish oil supplementation is a relatively safe and cheap alternative to either increased fish consumption with risks of mercury and lipid soluble toxins or more expensive algae-derived DHA supplementation. We hypothesize that: 1) Fish oil supplementation will synergize with the antioxidant curcumin and work as well or better than DHA in our AD model in controlling synaptic marker loss. 2) Fish oil will have similar anti-amyloid activities as DHA, but also induce TTR and be more effective in controlling amyloid. 3) EPA supplementation will induce only a subset of the protective effects of DHA. 4) Fish oil or DHA will increase principal investigator3-K pathway inhibition of GSK36 and tau pathology. We propose to test these hypotheses in transgenic and culture models with and without baseline omega-3 depletion providing more information on mechanism, active ingredient and the utility of marine oil and antioxidant supplementation relevant to the prevention and treatment of Alzheimer's disease.

描述（由申请人提供）：食用鱼类可降低阿尔茨海默病（AD）风险，这可能是由于长链欧米茄3脂肪酸（二十碳五烯酸（EPA）和二十二碳六烯酸（DHA））。实验室食物通常含有丰富的大豆和鱼，并且是足够的ω-3脂肪酸，这引起了食物中的ω-3是否影响实验室模型中的AD发病机制的问题。将老年APPsw AD模型小鼠置于以红花油作为主要脂肪的DHA耗尽的“坏”饮食中。没有证据表明神经元或突触素损失，DHA消耗增加了氧化损伤，半胱天冬酶切割肌动蛋白和PSD-95和树突棘肌动蛋白结合蛋白，dreplastin的缺陷。该效应是转基因依赖性的，表明“坏”饮食允许选择性APP转基因诱导的突触后缺陷。只有接受“不良”饮食的Tg（+）小鼠出现了与突触后功能和记忆相关的mRNA和蛋白质的严重缺陷，包括调节半胱天冬酶和tau激酶激活的神经保护主要研究者3 K p85。膳食DHA的神经保护作用是来自于对磷脂酰丝氨酸水平和主要代谢物3-K的调节，还是来自于脂氧合酶衍生的DHA代谢物（神经保护素D1），目前尚不清楚。补充DHA也能减少淀粉样蛋白病变，但相关机制仍不清楚：DHA不会诱导甲状腺素运载蛋白（TTR），TTR是一种可减少AD病变的抗淀粉样蛋白，据报道是由鱼油诱导的。目前，鱼油补充剂是一种相对安全和廉价的替代品，既可以增加鱼类消费，又可以增加汞和脂溶性毒素的风险，也可以增加更昂贵的藻类衍生DHA补充剂。我们假设：1）鱼油补充剂将与抗氧化剂姜黄素协同作用，并且在我们的AD模型中在控制突触标志物损失方面与DHA一样好或更好。2)鱼油将具有与DHA类似的抗淀粉样蛋白活性，但也诱导TTR，并且在控制淀粉样蛋白方面更有效。3)EPA补充剂只能诱导DHA保护作用的一部分。4)鱼油或DHA将增加GSK 36和tau病理的主要代谢物3-K途径抑制。我们建议在有和没有基线omega-3耗竭的转基因和培养模型中测试这些假设，提供更多关于预防和治疗阿尔茨海默病的机制，活性成分和海洋油和抗氧化剂补充剂的效用的信息。