Dietary Interventions in Alzheimer’s Disease
阿尔茨海默病的饮食干预
基本信息
- 批准号:10679129
- 负责人:
- 金额:$ 4.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3xTg-AD mouseAPP-PS1AffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAlzheimer&aposs disease therapyAmericanAmino AcidsAnimal ModelAnimalsAutophagocytosisBiology of AgingBrainBranched-Chain Amino AcidsCaloric RestrictionCaloriesCatabolismCause of DeathCell physiologyChronic DiseaseCognitionCognitive deficitsComplexConsumptionCyclic AMP-Dependent Protein KinasesDataDefectDementiaDepositionDevelopmentDietDietary InterventionDisease ProgressionEatingEconomic BurdenEnergy IntakeEssential Amino AcidsFRAP1 geneFacultyFastingFellowshipFoodGliosisGraduate DegreeHealthHealthcare SystemsHourHumanImpaired cognitionIncidenceIndividualInterventionIsoleucineKeto AcidsLeucineLifeLinkLongevityMediatingMentorshipMetabolicMetabolismModelingMolecularMusNeurofibrillary TanglesNutrientOxidoreductasePathogenesisPathologicPharmaceutical PreparationsPharmacologic SubstancePhosphotransferasesProtein KinaseProtein-Restricted DietProteinsPublic HealthRegimenResearchRisk FactorsRoleSignal TransductionSynapsesTestingTrainingUnited StatesValineWild Type MouseWorkabeta accumulationaging populationcareerdietarydietary excessdietary restrictionearly onseteffective therapyexperimental studyfeedingflyhealthspanhealthy aginghuman old age (65+)improvedinhibition of autophagyinsightinterestlaboratory experimentmembermouse modelmultiple omicspharmacologicpreventresponseskillssmall molecule inhibitortau Proteinstenure track
项目摘要
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.
项目摘要慢性病是老龄化人口中的一个重大问题,造成巨大的
给世界各地的医疗保健系统带来经济负担。阿尔茨海默病(AD)是最常见的
痴呆症,影响多达580万65岁及以上的美国人,是导致
美国的死亡案例。由于年龄是发展为阿尔茨海默病的最大风险因素,人们对这种可能性非常感兴趣
通过干预延缓或延缓衰老来靶向阿尔茨海默病。卡路里限制(CR)可以减缓或预防AD
动物模型,但低卡路里饮食是出了名的难以维持。在这项提案中,我将检查饮食是否
模仿传统CR饮食的养生法和药物,但更容易坚持,可以减缓或
预防阿尔茨海默病的发生发展。
来自拉明实验室和其他实验室的研究表明,蛋白质限制(PR)可以改善许多方面
改善人类和小鼠的代谢健康,并延长小鼠的寿命,这可能部分是通过减少
雷帕霉素复合体1的氨基酸敏感激酶机制靶点mTORC1的活性
自噬的关键调控因子。在初步研究中,我发现PR降低了大脑mTORC1的活性,并
激活自噬,减缓或阻止3xTg中认知能力下降和AD病理的进展
阿尔茨海默病小鼠模型。我们的实验室已经证明限制支链氨基酸(支链氨基酸;亮氨酸,
异亮氨酸、缬氨酸)概括了PR的新陈代谢益处,延长了寿命。支链氨基酸分解代谢缺陷,
或过量饮食中的支链氨基酸,可能通过增加大脑中支链氨基酸水平,激活
MTORC1,并抑制自噬。然而,个别支链氨基酸在这些影响中的作用尚不清楚。
我将确定限制蛋白质或亮氨酸的效果,这是最强烈的必需氨基酸
在APP/PS1小鼠模型中,对代谢健康、认知、AD病理和自噬等方面的mTORC1感到痛苦
与3xTg小鼠相比,AD小鼠在晚年出现认知缺陷。我还将测试是否降低支链氨基酸水平
通过药物刺激支链氨基酸分解代谢降低大脑支链氨基酸水平,抑制大脑mTORC1
发出信号并促进自噬,概括限制饮食的有益影响。最后,利用DISTINCT
饲喂方案I将确定是否延长每日禁食时间,哪些CR动物在实验室接受
实验,可以概括出CR饮食对AD发展和进展的有益影响。
这些拟议的目标将共同解决长期存在的问题,即饮食干预如何
影响阿尔茨海默病的发生发展。我将在我的导师的指导下完成这项奖学金
发起人,达德利·拉明博士,衰老生物学、新陈代谢和mTOR信号方面的专家,也是我的共同发起人,
世界领先的阿尔茨海默病专家Luigi Puglielli博士说。完成这些目标和随之而来的
个性化的培训计划将帮助我培养成为一名成功的终身教职教师所需的技能
成员主要研究衰老和阿尔茨海默氏症的生物学。
项目成果
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