Novel strategy to enrich brain DHA through diet: Potential application for the prevention of Alzheimer's disease

阿尔茨海默病(AD)是导致痴呆症的主要原因，影响着大约500万人 目前的美国人。预计到2050年，它将影响1600万美国人，并使 经济规模为1.1万亿美元。退伍军人中阿尔茨海默病的患病率比一般人高得多 因为一系列危险因素，包括年龄，创伤性脑损伤， 抑郁症和创伤后应激障碍在退伍军人中更为普遍。虽然没有 AD的有效治疗目前，在动物模型上的几项研究表明是有益的 二十二碳六烯酸(DHA)的作用，它是唯一集中在大脑中的，而且是 已知对其功能至关重要。然而，使用目前可用的DHA的临床试验 补充(鱼油、磷虾油、藻油、乙酯等)以改善患者的认知功能 一直令人失望。我们推测，这次失败是由于这些人不能 以推荐的安全剂量补充大脑DHA，因为它们都是 以三酰甘油(TAG)的形式吸收，而不是以磷脂的形式吸收 血脑屏障(BBB)的转运蛋白。我们最近已经证明了饮食 溶血磷脂酰胆碱(LPC)形式的DHA，其以磷脂形式被吸收， 不仅在低剂量下丰富大脑DHA，还能改善小鼠的认知和空间记忆 正常的小鼠。目前的提案将探索LPC和其他溶血磷脂的潜力 (LPL)在丰富大脑DHA和预防阿尔茨海默病小鼠模型中的作用。 在目标1中，我们将检验饮食DHA-溶血磷脂(LPL)优于 TAG-DHA(如鱼油)或天然磷脂DHA(如磷虾油)丰富大脑 DHA和改善正常小鼠的认知功能。此外，极头的影响 LPL基团(胆碱、乙醇胺或丝氨酸)以及二十碳五烯酸的作用 将测定酸(EPA)，以确定最有效的改善大脑功能的LPL。 在目标2中，我们将检验低剂量LPL-DHA治疗的假设(在 目的1)在双转基因AD小鼠模型中预防或延缓AD的发生。 三个月大的APPsWE/PS1ΔE9小鼠将分别接受LPL-DHA或TAG-DHA治疗 每日剂量40 mg DHA/kg，连续9个月，以及对认知行为、记忆和 神经病理学将会被确定。预计LPL-DHA而不是TAG-DHA将 在这些低剂量下减轻AD的病理症状。 在目标3中，我们将确定LPL-DHA有益效果的潜在机制， 与目前可用的DHA补充剂相比，在丰富大脑DHA和在 改善大脑功能。需要检验的假设包括：a)代谢优势 LPL-DHA的作用是由于它能够穿越肠道屏障和血脑屏障，b) LPL-DHA比游离DHA更抗炎，c)LPL-DHA在 大脑比游离DHA，和d)LPC-DHA贡献胆碱，胆碱是 乙酰胆碱，除DHA外，对大脑功能和AD有多方面的影响 发展。 这些研究的成功完成可能会导致一种新的营养治疗策略 预防和治疗阿尔茨海默病以及人群中的其他神经炎症性疾病 总的来说，尤其是在退伍军人中。

Alzheimer’s disease (AD) is the leading cause of dementia, and affects about 5 million Americans at present. It is projected to afflict 16 million Americans by 2050 and cost the economy $1.1 trillion. The prevalence of AD is much greater in veterans than in the general population because of a constellation of risk factors including age, traumatic brain injury, depression, and PTSD all of which are more prevalent in the veterans. While there is no effective treatment for AD at present, several studies in animal models have shown beneficial effects of docosahexaenoic acid (DHA) which is uniquely concentrated in the brain, and is known to be essential for its function. However, clinical trials using the currently available DHA supplements (fish oil, krill oil, algal oil, ethyl esters etc) to improve cognitive function in patients have been disappointing. We postulate that this failure is due to the inability of these supplements to enrich brain DHA at the recommended safe doses, because they are all absorbed in the form of triacylglycerol (TAG) rather than in the phospholipid form required by the transporter at the blood brain barrier (BBB). We have recently demonstrated that dietary DHA in the form of lysophosphatidylcholine (LPC), which is absorbed in the phospholipid form, not only enriches brain DHA at low doses, but also improves cognition and spatial memory in normal mice. The current proposal will explore the potential of LPC and other lysophospholipids (LPL) in enriching brain DHA and in the prevention of AD in a mouse model of the disease. In Aim 1, we will test the hypothesis that dietary DHA-lysophospholipids (LPL) are superior to either TAG-DHA (as in fish oil) or natural phospholipid DHA (as in krill oil) in enriching the brain DHA and improving cognitive function in normal mice. In addition, the effect of the polar head group of the LPL (choline, ethanolamine, or serine), as well as the effect of eicosapentaenoic acid (EPA) will be determined, to identify the most efficient LPL for improving the brain function. In Aim 2, we will test the hypothesis that treatment with a low dose of LPL-DHA (identified in Aim 1) will prevent or delay the development of AD in a double transgenic mouse model of AD. Three-month-old APPswe/PS1ΔE9 mice will be treated with either LPL-DHA or TAG-DHA at a daily dose of 40 mg DHA/kg for 9 months, and the effects on cognitive behavior, memory, and neuropathology will be determined. It is anticipated that LPL-DHA, but not TAG-DHA would alleviate the pathological symptoms of AD at these low doses. In Aim 3, we will determine the mechanisms underlying the beneficial effects of LPL-DHA, compared to the currently available supplements of DHA, in enriching brain DHA and in improving brain function. The hypotheses to be tested include: a) that the metabolic advantage of LPL-DHA is due its ability to cross both the intestinal barrier and blood brain barrier, b) that LPL-DHA is more anti-inflammatory than free DHA, c) that LPL-DHA is oxidized less rapidly in the brain than free DHA, and d) LPC-DHA contributes choline, the essential component of acetylcholine, in addition to DHA, which has pluripotent effects on brain function and AD development. Successful completion of these studies could lead to a novel nutraceutical strategy for the prevention and treatment of AD, as well as other neuro-inflammatory diseases in the population in general, and in the veterans in particular.