Can Omega 3 fatty acids Slow Alzheimer Pathogenesis?

描述(由申请人提供)：食用鱼类可降低阿尔茨海默病(AD)的风险，可能是由于长链欧米茄3脂肪酸(EPA)和二十二碳六烯酸(DHA)。实验室排骨通常含有丰富的大豆和鱼类，是足够的omega-3脂肪酸，这引发了这样一个问题：在实验室模型中，食物中的omega 3是否会影响AD的发病机制。老年APPsw AD模型小鼠被置于以红花油为主要脂肪的DHA耗竭的“坏”饮食中。在没有证据表明神经元或突触素丢失的情况下，DHA的枯竭增加了氧化损伤、caspase裂解的肌动蛋白以及PSD-95和树突状脊椎肌动蛋白结合蛋白Drebrin的缺失。这种影响是转基因依赖的，这表明“坏”饮食对选择性APP转基因诱导的突触后缺陷是允许的。只有“坏”饮食的TG(+)小鼠在与突触后功能和记忆相关的mRNA和蛋白质方面出现了重大缺陷，包括神经保护性首席研究员3K P85，它同时调节caspase和tau激酶的激活。饮食中DHA的神经保护作用是来自对磷脂酰丝氨酸水平和主要研究者3-K的调节，还是来自脂肪氧合酶衍生的DHA代谢物(神经保护素DL)，目前尚不清楚。补充DHA也可减少淀粉样蛋白的病理改变，但相关机制尚不清楚：DHA不能诱导转甲状腺激素(TTR)，这是一种抗淀粉样蛋白，可减少AD的病理改变，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方案，可以替代有汞和脂溶毒素风险的鱼类消费量增加，或更昂贵的藻类来源的DHA补充剂。我们假设：1)在我们的AD模型中，补充鱼油将与抗氧化剂姜黄素协同作用，在控制突触标志物丢失方面的作用与DHA相同或更好。2)鱼油具有与DHA相似的抗淀粉样蛋白活性，但也可诱导TTR，对淀粉样蛋白的控制更为有效。3)补充EPA只会诱导DHA的保护作用的一部分。4)鱼油或DHA可增加3-K通路对GSK36和tau病理的抑制作用。我们建议在有和没有omega-3基线耗竭的转基因和培养模型中测试这些假设，提供更多关于机制、活性成分以及与预防和治疗阿尔茨海默病相关的海洋油和抗氧化剂补充剂的用途的信息。

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.