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.

慢性病是人口老龄化的一个重要问题， 给世界各地的医疗保健系统带来经济负担。阿尔茨海默氏病（AD）是阿尔茨海默氏病的最常见形式。 痴呆症，影响多达580万65岁及以上的美国人，是第六大原因， 死亡在美国。由于年龄是发展AD的最大风险因素，因此人们对这种可能性非常感兴趣。 通过干预来减缓或延缓衰老。热量限制（CR）可以减缓或预防AD， 动物模型，但众所周知，低热量饮食难以维持。在这个建议中，我将研究饮食是否 方案和药物，模仿传统的CR饮食的方面，但更容易坚持，可以减缓或 预防AD的发生和发展。 来自Lamming实验室和其他人的研究表明，蛋白质限制（PR）改善了许多方面 在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（mTORC 1）的氨基酸敏感性激酶机制靶标的活性，其是一种 自噬的关键调节因子在初步研究中，我发现PR降低了大脑mTORC 1的活性， 激活自噬，并减缓或预防3xTg中的认知下降和AD病理学进展。 AD小鼠模型。我们的实验室已经表明，限制支链氨基酸（支链氨基酸;亮氨酸， 异亮氨酸、缬氨酸）概括了PR的代谢益处并延长寿命。支链氨基酸催化剂的缺陷， 或过量的饮食BCAA，可能通过增加大脑中的BCAA水平，激活 mTORC 1和抑制自噬。然而，个体BCAA在这些效应中的作用尚不清楚。 我将确定限制蛋白质或亮氨酸的影响，亮氨酸是最强的必需氨基酸 在APP/PS1小鼠模型中激动mTORC 1，对代谢健康、认知、AD病理学和自噬的影响 AD，其在生命中比3xTg小鼠晚发展认知缺陷。我还将测试降低支链氨基酸水平 通过药理学刺激BCAA catalysts降低BCAA的大脑水平，抑制大脑mTORC 1 信号和促进自噬，重现限制性饮食的有益效果。最后，利用不同的 饲养方案I将确定是否延长每日禁食，CR动物在实验室中接受 实验，可以概括CR饮食对AD的发展和进展的有益作用。 总之，这些拟议的目标将解决长期存在的问题，即饮食干预如何能够 影响AD的发生和发展。我将在我的导师的指导下完成这项研究。 赞助人，达德利·拉明博士，一位衰老生物学、新陈代谢和mTOR信号传导方面的专家，以及我的共同赞助人， 博士Luigi Puglielli，世界领先的阿尔茨海默病专家。完成这些目标和伴随的 个性化的培训计划将帮助我发展成为一名成功的终身教职员工所需的技能 委员会成员专注于衰老和阿尔茨海默病的生物学。