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

通过饮食丰富大脑 DHA 的新策略：预防阿尔茨海默病的潜在应用

• 批准号: 10265364
• 负责人: PAPASANI V SUBBAIAH
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265364
• 关键词: Acetylcholine; Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; American; Animal Model; Animals; Anti-Inflammatory Agents; Behavior; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; Choline; Clinical Trials; Cognition; Cognitive; Data; Dementia; Development; Diet; Disease; Disease model; Docosahexaenoic Acids; Docosahexaenoic acid supplement; Dose; Eicosapentaenoic Acid; Esters; Ethanolamines; Euphausiacea; Failure; Fish Oils; General Population; Head; Hydrolysis; Intestinal Absorption; Intestines; Lead; Lysophosphatidylcholines; Lysophospholipids; Memory; Mental Depression; Metabolic; Mus; Nerve Tissue; Nutraceutical; Oils; Omega-3 Fatty Acids; Oxides; Parkinson Disease; Pathologic; Patients; Phospholipids; Population; Post-Traumatic Stress Disorders; Prevalence; Prevention; Prevention strategy; Rattus; Risk Factors; Schizophrenia; Serine; Symptoms; Testing; Transgenic Mice; Traumatic Brain Injury; Triglycerides; Veterans; absorption; base; brain tissue; cognitive function; cost; dietary; effective therapy; effectiveness testing; high risk; improved; intestinal barrier; mouse model; nervous system disorder; neuroinflammation; neuropathology; novel; novel strategies; prevent; spatial memory; success

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.

阿尔茨海默病 (AD) 是导致痴呆症的主要原因，影响约 500 万人 目前，预计到 2050 年将有 1600 万美国人受到影响，并为此付出了巨大的代价。 经济 1.1 万亿美元。退伍军人中 AD 的患病率远高于一般人群。 由于一系列危险因素，包括年龄、创伤性脑损伤、 抑郁症和创伤后应激障碍（PTSD）在退伍军人中更为普遍，但没有。 目前针对AD的有效治疗方法，多项动物模型研究显示有益 二十二碳六烯酸（DHA）的作用，它独特地集中在大脑中，并且 然而，目前可用的 DHA 的临床试验表明其功能至关重要。 补充剂（鱼油、磷虾油、藻油、乙酯等）可改善患者的认知功能 我们假设这次失败是由于这些人的无能。 按推荐的安全剂量补充大脑 DHA，因为它们都是 以三酰甘油 (TAG) 形式吸收，而不是以磷脂形式吸收 我们最近证明了饮食中的血脑屏障（BBB）转运蛋白。 DHA 以溶血磷脂酰胆碱 (LPC) 形式存在，以磷脂形式被吸收， 不仅可以低剂量补充大脑DHA，还能提高认知能力和空间记忆能力 目前的提案将探索 LPC 和其他溶血磷脂的潜力。 (LPL) 可以在小鼠模型中丰富大脑 DHA 并预防 AD。 在目标 1 中，我们将检验以下假设：膳食 DHA-溶血磷脂 (LPL) 优于 TAG-DHA（如鱼油）或天然磷脂 DHA（如磷虾油）可丰富大脑 此外，DHA还有改善正常小鼠认知功能的作用。 LPL（胆碱、乙醇胺或丝氨酸）组，以及二十碳五烯酸的作用 将测定酸（EPA），以确定改善大脑功能最有效的LPL。 在目标 2 中，我们将检验以下假设：用低剂量的 LPL-DHA 进行治疗（在 目标 1) 将预防或延缓 AD 双转基因小鼠模型中 AD 的发展。 三个月大的 APPswe/PS1ΔE9 小鼠将接受 LPL-DHA 或 TAG-DHA 治疗，治疗时间为 每天服用 40 毫克 DHA/kg，持续 9 个月，以及对认知行为、记忆力和认知能力的影响 预计将确定 LPL-DHA，而不是 TAG-DHA。 在这些低剂量下缓解 AD 的病理症状。 在目标 3 中，我们将确定 LPL-DHA 有益作用的机制， 与目前可用的DHA补充剂相比，在丰富大脑DHA和 改善大脑功能。要检验的假设包括：a) 代谢优势。 LPL-DHA 的存在是因为它能够穿过肠屏障和血脑屏障，b) LPL-DHA 比游离 DHA 具有更强的抗炎作用，c) LPL-DHA 在体内的氧化速度较慢 d) LPC-DHA 为大脑提供胆碱，胆碱是人体的重要组成部分 除 DHA 外，乙酰胆碱对大脑功能和 AD 具有多能作用 发展。 这些研究的成功完成可能会产生一种新的营养保健策略 预防和治疗人群中的 AD 以及其他神经炎症性疾病 一般来说，特别是退伍军人。