Ketogenic diet approaches to slow disease progression in a rat model of Alzheimer's disease

生酮饮食方法可减缓阿尔茨海默病大鼠模型的疾病进展

基本信息

批准号：
9977496
负责人：
Pamela J Lein
金额：
$ 43.18万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977496
关键词：
Adopted Affect Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Blood Brain Brain region Caloric Restriction Carbohydrates Cerebellum Consumption Control Groups Dementia Diet Disease Disease Progression Elderly Energy Intake Fasting Fatty acid glycerol esters Female Glucose Hand Strength High Fat Diet Hippocampus (Brain)Impaired cognition Impairment Individual Inflammation Intermittent fasting Ketones Ketosis Life Style Link Longevity Measures Memory Memory impairment Metabolic Metabolic stress Mitochondria Motor Mus Pathogenesis Patients Pharmaceutical Preparations Physiological Rattus Reporting Risk Rodent Model Running Severities Severity of illness Signal Transduction Source Symptoms Testing United States age related neurodegeneration behavior measurement behavior test beta-Hydroxybutyrate cognitive function cohort congenic effective therapy entorhinal cortex feeding improved inflammatory marker ketogenic diet ketogentic male mitochondrial dysfunction motor deficit motor function improvement mouse model neuroinflammation novel object recognition preservation prevent response

项目摘要

Project Summary Alzheimer’s disease is the most common age-related neurodegenerative disease, and there is a clear need to develop effective approaches to treat or prevent the cognitive impairment that is the prominent symptom of this disease. Neuroinflammation and mitochondrial impairments have been implicated in the pathogenesis of Alzheimer’s disease, and ketogenic diets have been reported to decrease inflammation and enhance mitochondrial function. This has led to speculation that ketogenic diets may provide an effective approach to treat Alzheimer’s disease. In support of this idea, short-term (≤3 months) studies have shown that ketogenic diets improve motor function in mouse models of Alzheimer’s disease. However, memory was not improved with this diet, perhaps because the impact of the ketogenic diet was blunted by the ad libitum feeding approach used in these studies. There is growing appreciation that physiological response to a high fat diet is likely dependent on level of energy intake. Ketogenic diets are inherently high in fat and ad libitum feeding of a high fat diet induces a metabolic stress that may impair cognitive function. To investigate the physiological impact of these diets independent of differences in energy intake, we fed mice a ketogenic diet in isocaloric amounts to a control diet and found that the ketogenic diet increased life span and preserved memory and motor function with advanced age. It remains to be determined whether this feeding approach, which produces sustained ketosis, would also improve memory in rodent models of Alzheimer’s disease. Calorie restriction and intermittent fasting, which produce intermittent periods of ketosis, have also been reported to mitigate cognitive impairments in mouse models of Alzheimer’s disease. This raises the possibility that ketosis does not need to be continuous to have a beneficial impact on memory, which if true, would provide a lifestyle change more likely to be adopted by at-risk individuals. Sustained or intermittent increases in blood ketone levels with consumption of a ketogenic diet may be particularly beneficial if they lessen inflammation. Thus, we hypothesize that isocaloric ketogenic diet feeding approaches that produce either sustained or intermittent ketosis will decrease neuroinflammation and delay the onset or lessen the severity of disease progression in the TgF344-AD rat model of Alzheimer’s disease. We propose two specific aims to test this hypothesis: 1) determine if an isocaloric ketogenic diet feeding approach slows disease progression in the TgF344-AD rat; 2) determine if intermittent feeding of a ketogenic diet is sufficient to delay the onset or lessen the severity of memory and motor deficits in the TgF344-AD rat. These studies will take an important step toward determining if ketogenic diet approaches provide a viable strategy to treat or prevent Alzheimer’s disease.

项目概要阿尔茨海默病是最常见的与年龄相关的神经退行性疾病，显然需要制定有效的方法来治疗或预防认知障碍，这是这种疾病的突出症状神经炎症和线粒体损伤与该病的发病机制有关。据报道，阿尔茨海默病和生酮饮食可以减少炎症并增强这导致人们猜测生酮饮食可能提供一种有效的方法。短期（≤3个月）研究表明生酮可以治疗阿尔茨海默病。饮食可以改善阿尔茨海默病小鼠模型的运动功能，但记忆力却没有改善。采用这种饮食，可能是因为生酮饮食的影响被随意喂养的方法削弱了人们越来越认识到，高脂肪饮食可能会产生生理反应。取决于能量摄入水平，生酮饮食本质上脂肪含量高，并且可以随意进食。脂肪饮食会引起可能损害认知功能的代谢应激，以研究其生理影响。在这些饮食中，与能量摄入的差异无关，我们给小鼠喂食等热量的生酮饮食与对照饮食相比，发现生酮饮食可以延长寿命并保留记忆力和运动能力随着年龄的增长，这种喂养方式是否会产生功能还有待确定。持续的酮症还可以改善阿尔茨海默病啮齿动物模型的记忆力。据报道，间歇性禁食会产生间歇性酮症，也可以减轻阿尔茨海默病小鼠模型的认知障碍增加了酮症造成的可能性。不需要持续对记忆产生有益的影响，如果这是真的，将提供一种生活方式血酮持续或间歇性增加的风险个体更有可能采取这种改变。如果生酮饮食可以减轻炎症，那么这种水平可能特别有益。提倡等热量生酮饮食喂养方法，可产生持续或间歇性的效果酮症将减少神经炎症并延迟发病或减轻疾病进展的严重程度我们提出了两个具体目标来检验这一假设：1) 确定等热量生酮饮食喂养方法是否可以减缓 TgF344-AD 大鼠的疾病进展 2) 确定生酮饮食的间歇喂养是否足以延迟发作或减轻严重程度这些研究将朝着确定 TgF344-AD 大鼠的记忆和运动缺陷迈出重要一步。生酮饮食方法是否提供了治疗或预防阿尔茨海默病的可行策略。