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.

项目摘要阿尔茨海默氏病是最常见的与年龄相关的神经退行性疾病，显然需要开发有效的方法来治疗或预防认知障碍，这是重大症状疾病。神经炎症和线粒体障碍已在发病机理中暗示据报道，阿尔茨海默氏病和生酮饮食可减少感染并增强线粒体功能。这导致人们猜测，生酮饮食可能会提供有效的方法治疗阿尔茨海默氏病。为了支持这个想法，短期（≤3个月）的研究表明生酮饮食改善了阿尔茨海默氏病小鼠模型的运动功能。但是，记忆没有得到改善使用这种饮食，也许是因为生酮饮食的影响被多重喂养方法削弱了这些研究用于这些研究。人们越来越感谢对高脂饮食的身体反应可能是取决于能量摄入水平。生酮饮食本质上是高脂肪和高脂肪的高度喂养脂肪饮食会诱导可能损害认知功能的代谢压力。调查身体影响在这些饮食中与能量摄入差异无关控制饮食，发现生酮饮食增加了寿命，保留记忆力和运动高年龄的功能。是否会产生这种喂养方法是否会确定持续的酮症还可以改善阿尔茨海默氏病啮齿动物模型的记忆。卡路里限制以及产生间歇性酮症时期的间歇性禁食，也据报道减轻阿尔茨海默氏病小鼠模型中的认知障碍。这增加了酮症确实有可能不需要连续对记忆产生有益的影响，如果是真的，那将提供一种生活方式更有可能被高危个人采用。血酮持续或间歇性增加消耗生酮饮食的水平如果炎症较少，可能会特别有益。那，我们假设是产生持续或间歇性的等级生酮饮食喂养方法酮症将减少神经炎症并延迟发作或更少阿尔茨海默氏病的TGF344-AD大鼠模型。我们提出了两个特定的目的来检验这一假设：1）确定等热生酮饮食进食方法是否会减慢TGF344-AD大鼠的疾病进展； 2）确定生酮饮食的间歇性进食是否足以延迟发作或更少内存和电动机在TGF344-AD大鼠中定义。这些研究将朝着确定的重要一步如果生酮饮食方法为治疗或预防阿尔茨海默氏病提供了可行的策略。