Dietary Interventions in Alzheimer’s Disease

阿尔茨海默病的饮食干预

• 批准号: 10679129
• 负责人: Reji Babygirija
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679129
• 关键词: 3xTg-AD mouse; APP-PS1; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' s disease therapy; American; Amino Acids; Animal Model; Animals; Autophagocytosis; Biology of Aging; Brain; Branched-Chain Amino Acids; Caloric Restriction; Calories; Catabolism; Cause of Death; Cell physiology; Chronic Disease; Cognition; Cognitive deficits; Complex; Consumption; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Dementia; Deposition; Development; Diet; Dietary Intervention; Disease Progression; Eating; Economic Burden; Energy Intake; Essential Amino Acids; FRAP1 gene; Faculty; Fasting; Fellowship; Food; Gliosis; Graduate Degree; Health; Healthcare Systems; Hour; Human; Impaired cognition; Incidence; Individual; Intervention; Isoleucine; Keto Acids; Leucine; Life; Link; Longevity; Mediating; Mentorship; Metabolic; Metabolism; Modeling; Molecular; Mus; Neurofibrillary Tangles; Nutrient; Oxidoreductase; Pathogenesis; Pathologic; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Protein Kinase; Protein-Restricted Diet; Proteins; Public Health; Regimen; Research; Risk Factors; Role; Signal Transduction; Synapses; Testing; Training; United States; Valine; Wild Type Mouse; Work; abeta accumulation; aging population; career; dietary; dietary excess; dietary restriction; early onset; effective therapy; experimental study; feeding; fly; healthspan; healthy aging; human old age (65+); improved; inhibition of autophagy; insight; interest; laboratory experiment; member; mouse model; multiple omics; pharmacologic; prevent; response; skills; small molecule inhibitor; tau Proteins; tenure track

PROJECT SUMMARY Chronic diseases are a significant problem in aging population causing immense economic burden to healthcare systems around the world. Alzheimer’s disease (AD) is the most common form of dementia, affecting as many as 5.8 million Americans who are aged 65 and older and is the sixth leading cause of death in the United States. As age is the greatest risk factor in developing AD, there is great interest in the possibility of targeting AD through interventions that slow or delay aging. Calorie restriction (CR) can slow or prevent AD in animal models, but reduced calorie diets are notoriously difficult to sustain. In this proposal, I will examine if dietary regimens and drugs that mimic aspects of a traditional CR diet, but which are easier to adhere to, can slow or prevent the development and progression of AD. Studies from the Lamming lab and others have shown that protein restriction (PR) improves many aspects of metabolic health in both humans and mice, and extends mouse lifespan, likely in part through reducing the activity of the amino acid sensitive kinase mechanistic Target Of Rapamycin complex 1 (mTORC1), which is a key regulator of autophagy. In preliminary studies, I have found that PR reduces brain mTORC1 activity and activates autophagy, and slows or prevents cognitive decline and the progression of AD pathology in the 3xTg mouse model of AD. Our lab has shown that restriction of the branched chain amino acids (BCAAs; leucine, isoleucine, valine) recapitulates the metabolic benefits of PR and extends lifespan. Defects in BCAA catabolism, or excess dietary BCAAs, may drive the pathogenesis of AD by increasing BCAA levels in the brain, activating mTORC1, and inhibiting autophagy. However, the role of individual BCAAs in these effects are unknown. I will determine the effects of restricting protein or leucine, the essential amino acid that most strong agonizes mTORC1, on metabolic health, cognition, AD pathology, and autophagy in the APP/PS1 mouse model of AD, which develops cognitive deficits later in life than the 3xTg mice. I will also test if reducing levels of BCAAs via pharmacological stimulation of BCAA catabolism reduces brain levels of BCAAs, inhibiting brain mTORC1 signaling and boost autophagy, recapitulating the beneficial effects of restrictive diets. Finally, utilizing distinct feeding regimens I will determine if prolonged daily fasting, which CR animals are subjected to in laboratory experiments, can recapitulate the beneficial effects of a CR diet on the development and progression of AD. Together, these proposed aims will address long-standing questions about how dietary interventions can affect the development and progression of AD. I will be completing this fellowship under the mentorship of my sponsor, Dr. Dudley Lamming, an expert in aging biology, metabolism, and mTOR signaling, and my co-sponsor, Dr. Luigi Puglielli, a world-leading expert in Alzheimer’s disease. Completing these aims and the accompanying individualized training plan will help me develop the skills necessary to become a successful tenure track faculty member focused on the biology of aging and Alzheimer’s disease.

项目摘要慢性疾病是人口老龄化导致巨大的重大问题 世界各地的医疗保健系统的经济燃烧。阿尔茨海默氏病（AD）是最常见的形式 痴呆症，多达580万65岁以上的美国人，是第六个主要原因 在美国死亡。由于年龄是开发广告的最大风险因素，因此可能性很大 通过缓慢或延迟衰老的干预措施来靶向广告。卡路里限制（CR）可以放慢或阻止广告 动物模型，但众所周知，降低卡路里饮食很难维持。在此提案中，我将检查是否饮食 模仿传统CR饮食方面的方案和药物，但更容易遵守，可以放慢或 防止AD的发展和发展。 Lamming Lab和其他的研究表明，蛋白质限制（PR）改善了许多方面 人类和小鼠的代谢健康，并延长小鼠的寿命，可能部分通过减少 雷帕霉素复合物1（MTORC1）的氨基酸敏感激酶机械靶标的活性，这是一个 自噬的关键调节器。在初步研究中，我发现PR降低了脑MTORC1活性和 激活自噬，减慢或阻止3XTG中AD病理的认知能力下降和进展 AD的鼠标模型。我们的实验室表明，分支链氨基酸的限制（BCAA；亮氨酸， 异亮氨酸，Valine）概括了PR的代谢益处，并延长了寿命。 BCAA分解代谢缺陷， 或超过饮食BCAA，可能通过增加大脑的BCAA水平来驱动AD的发病机理，激活 mtorc1，并抑制自噬。但是，单个BCAA在这些效果中的作用尚不清楚。 我将确定限制蛋白质或亮氨酸的影响，蛋白质或亮氨酸是最强的必需氨基酸 在APP/PS1鼠标模型中，痛苦MTORC1，关于代谢健康，认知，AD病理学和自噬 与3XTG小鼠相比，在生活中发展的AD的定义以后定义。我还将测试是否降低BCAA的水平 通过药物刺激BCAA分解代谢可降低BCAA的大脑水平，抑制脑MTORC1 信号传导和增强自噬，概括了限制性饮食的有益作用。最后，使用独特的 喂养方案我将确定是否长时间的每日禁食，在实验室中受到CR动物的约束 实验可以概括CR饮食对AD发展和进展的有益影响。 这些提议的目标在一起将解决有关饮食干预如何如何的长期问题 影响AD的发展和发展。我将在我的指导下完成这一奖学金 赞助商Dudley Lamming博士是老化生物学，代谢和MTOR信号的专家，以及我的共同赞助商 Luigi Puglielli博士是阿尔茨海默氏病的世界领先专家。完成这些目标和参与 个性化的培训计划将帮助我发展成为成功的任期教师所需的技能 成员专注于衰老和阿尔茨海默氏病的生物学。