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; 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.

阿尔茨海默氏病（AD）是痴呆症的主要原因，影响约500万 目前美国人。预计到2050年，它将遭受1600万美国人的折磨，并花费 经济1.1万亿美元。退伍军人的AD的患病率要比一般要大得多 人口是由于一系列风险因素，包括年龄，创伤性脑损伤， 抑郁症和PTSD在退伍军人中更为普遍。虽然没有 目前，有效的AD治疗方法，在动物模型中进行了几项研究表明有益 二十六烯酸（DHA）的影响，它独特地集中在大脑中，是 知道其功能至关重要。但是，使用当前可用DHA的临床试验 补充剂（鱼油，磷虾油，藻类油，乙基酯等），以改善患者的认知功能 令人失望。我们假设这种失败是由于这些失败的原因 以建议的安全剂量以富含大脑DHA的补充剂，因为它们都是 以三酰基甘油（TAG）的形式吸收，而不是以 血脑屏障（BBB）的转运蛋白。我们最近证明了饮食 DHA以溶血磷脂酰胆碱（LPC）形式，以磷脂形式吸收， 不仅以低剂量丰富了脑DHA，还可以改善认知和空间记忆 正常小鼠。当前的建议将探讨LPC和其他溶物磷脂的潜力 （LPL）在富集脑DHA和预防疾病的小鼠模型中的AD中。 在AIM 1中，我们将检验以下假设：饮食中的DHA溶质磷脂（LPL）优于 富含大脑 DHA并改善正常小鼠的认知功能。另外，极性头的效果 LPL（胆碱，乙醇胺或丝氨酸）以及eicosapentaenoic的效果 将确定酸（EPA），以确定改善大脑功能的最有效的LPL。 在AIM 2中，我们将测试以低剂量LPL-DHA治疗的假设（在 AIM 1）将防止或延迟AD的双转基因小鼠模型中AD的发展。 三个月大的Appswe/ps1Δe9小鼠将在A处用LPL-DHA或TAG-DHA治疗 每日剂量为40 mg DHA/kg 9个月，对认知行为，记忆和 将确定神经病理学。预计LPL-DHA，但不会 减轻这些低剂量时AD的病理症状。 在AIM 3中，我们将确定LPL-DHA的有益作用的基础机制， 与当前可用的DHA补充剂相比，在丰富了脑DHA和 改善大脑功能。要测试的假设包括：a）代谢优势 LPL-DHA的能力越过肠壁和血脑屏障的能力，b） LPL-DHA比游离DHA更具抗炎作用，c）LPL-DHA在氧化中的氧化较低 大脑比游离DHA，D）LPC-DHA贡献胆碱，这是胆碱的重要组成部分 除DHA外，乙酰胆碱对脑功能和AD具有多能影响 发展。 这些研究的成功完成可能会导致一种新颖的营养策略 预防和治疗AD以及人群中其他神经炎症性疾病 通常，特别是在退伍军人中。