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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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 阿尔茨海默病是最常见的与年龄相关的神经退行性疾病， 制定有效的方法来治疗或预防认知障碍，这是这一问题的突出症状。 疾病神经炎症和线粒体损伤已被牵连的发病机制， 阿尔茨海默氏病和生酮饮食已被报道可以减少炎症并增强 线粒体功能这引起了人们的猜测，生酮饮食可能提供了一种有效的方法， 治疗老年痴呆症为了支持这一想法，短期（≤3个月）研究表明，生酮 饮食改善阿尔茨海默病小鼠模型的运动功能。然而，记忆力并没有得到改善， 采用这种饮食，可能是因为生酮饮食的影响被随意喂养方法减弱了 在这些研究中使用。越来越多的人认识到，高脂肪饮食可能会引起生理反应， 取决于能量摄入水平。生酮饮食本身就含有高脂肪， 高脂肪饮食引起代谢应激，可能损害认知功能。为了研究 在这些不依赖于能量摄入差异的饮食中，我们以等热量的量给小鼠喂食生酮饮食， 结果发现，生酮饮食延长了寿命，并保留了记忆和运动能力。 功能随着年龄的增长。目前还有待确定的是，这种喂养方法， 持续的酮症，也会改善阿尔茨海默病啮齿动物模型的记忆。热量限制 和间歇性禁食，产生间歇性酮症，也有报道说， 阿尔茨海默病小鼠模型的认知障碍。这就提出了酮症 不需要持续对记忆产生有益的影响，如果这是真的， 更有可能被处于危险中的人所采用。血酮持续或间歇性升高 如果它们减轻炎症，则与生酮饮食消费的水平可能特别有益。因此我们 假设等热量生酮饮食喂养方法产生持续或间歇性 酮症将减少神经炎症并延迟疾病进展的发作或减轻疾病进展的严重程度， TgF 344-AD大鼠阿尔茨海默病模型。我们提出了两个具体的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减缓TgF 344-AD大鼠的疾病进展; 2） 确定间歇性喂养生酮饮食是否足以延迟发作或减轻严重程度 TgF 344-AD大鼠的记忆和运动缺陷。这些研究将迈出重要的一步， 生酮饮食方法是否为治疗或预防阿尔茨海默病提供了可行的策略。