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

阿尔茨海默病（AD）是痴呆症的主要原因，影响约500万人 美国人目前预计到2050年将有1600万美国人受到影响， 经济1.1万亿美元。AD的患病率在退伍军人中比在普通人群中高得多。 人口，因为一系列的风险因素，包括年龄，创伤性脑损伤， 抑郁症和创伤后应激障碍这些都在退伍军人中更为普遍。虽然没有 目前，在动物模型中的几项研究已经显示出有益的 二十二碳六烯酸（DHA）的作用，它独特地集中在大脑中， 这对它的功能至关重要。然而，使用现有DHA的临床试验 补充剂（鱼油、磷虾油、藻油、乙酯等），以改善患者的认知功能 都令人失望我们假设，这种失败是由于这些 补充剂，以丰富大脑DHA在推荐的安全剂量，因为他们都是 以三酰甘油（TAG）的形式吸收，而不是以磷脂形式吸收， 血脑屏障（BBB）的转运蛋白。我们最近证明，饮食 溶血磷脂酰胆碱（LPC）形式的DHA，其以磷脂形式吸收， 不仅在低剂量下丰富大脑DHA，还能改善认知和空间记忆， 正常小鼠目前的提案将探索LPC和其他溶血磷脂的潜力 (LPL)在富含脑DHA和预防AD的小鼠疾病模型中。 在目标1中，我们将检验膳食DHA-溶血磷脂（LPL）上级 无论是TAG-DHA（如鱼油）或天然磷脂DHA（如磷虾油）在丰富大脑 DHA和改善正常小鼠的认知功能。此外，极头的作用 LPL组（胆碱，乙醇胺或丝氨酸），以及二十碳五烯酸的作用 将测定LPL对EPA的影响，以确定最有效的LPL用于改善脑功能。 在目标2中，我们将检验用低剂量LPL-DHA（在本发明中鉴定）治疗可降低低剂量LPL-DHA的假设。 目的1）在AD双转基因小鼠模型中预防或延缓AD的发展。 三个月大的APPswe/PS1ΔE9小鼠将用LPL-DHA或TAG-DHA以100 mg/kg的剂量进行治疗。 每日剂量为40 mg DHA/kg，持续9个月，以及对认知行为、记忆和 将确定神经病理学。预期LPL-DHA，而不是TAG-DHA， 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有益作用的潜在机制， 与目前可用的DHA补充剂相比， 改善大脑功能待检验的假设包括：a）代谢优势 LPL-DHA的显著增加是由于其穿过肠屏障和血脑屏障的能力，B） LPL-DHA比游离DHA更具有抗炎性，c）LPL-DHA在体内氧化较慢， d）LPC-DHA贡献胆碱，胆碱是大脑的基本成分， 乙酰胆碱，除DHA外，对脑功能和AD具有多能作用 发展 这些研究的成功完成可能会导致一种新的营养策略， 预防和治疗AD以及人群中的其他神经炎性疾病 尤其是退伍军人。

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.