Dietary manipulations in rabbits induce the cellular, neuropathological, and cognitive hallmarks of late-onset Alzheimer's Disease

兔子的饮食控制会诱发迟发性阿尔茨海默病的细胞、神经病理和认知特征

• 批准号: 10468188
• 负责人: BERNARD G. SCHREURS
• 金额: $ 54.89万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468188
• 关键词: Acetylcholinesterase; Adult; Affect; Alloxan; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Animals; Behavioral; Blood - brain barrier anatomy; Carrier Proteins; Characteristics; Chemicals; Cholesterol; Choline O-Acetyltransferase; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Complex; Data; Dementia; Dendritic Spines; Deposition; Diabetes Mellitus; Diet; Discrimination; Dose; Electrophysiology (science); Epidemiology; Fatty acid glycerol esters; Female; Goals; Hepatotoxicity; High Fat Diet; Hippocampus (Brain); Human; Hyperglycemia; Hypertension; Impaired cognition; Impairment; Late Onset Alzheimer Disease; Learning; Life Style; Long-Term Potentiation; Membrane; Memory; Microglia; Modeling; Morphology; Neurobiology; Neuronal Plasticity; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oryctolagus cuniculus; Pathology; Plants; Positioning Attribute; Predictive Value; Prefrontal Cortex; Publishing; Research; Risk Factors; Rodent Model; Serum; Slice; Smoking; Soybean Oil; Superoxide Dismutase; Synaptic plasticity; Testing; Transgenic Mice; Translating; Ventricular; abeta accumulation; cerebrovascular; clinically relevant; cognitive function; comorbidity; dietary manipulation; eyeblink conditioning; feeding; human old age (65+); hypercholesterolemia; improved; innovation; lard; lipid transport; long term memory; male; mouse model; prevent; sugar; tau Proteins; translational potential; vascular inflammation; young adult

Abstract: Despite the significant contributions of transgenic mouse models to our understanding of Alzheimer’s disease, NIA has concluded that these models may be “of poor predictive value in human clinical trials” [RFA- AG-21-003]. As a result, there is a need for new, innovative, non-rodent, mammalian models that better recapitulate the cellular, neuropathological, and cognitive hallmarks of late-onset Alzheimer’s Disease (LOAD). These should include models in which risk factors for LOAD can be systematically induced, and in which cognitive deficits that are the earliest hallmarks of LOAD can be assessed. There is convincing epidemiological evidence that diet and lifestyle are important determinants of cognitive function, but it is unclear how factors such as high cholesterol, obesity, and diabetes increase the likelihood of cognitive deficits. The purpose of the current proposal is to develop, characterize, and validate unconventional, mammalian models that recapitulate the cellular, neuropathological, and cognitive hallmarks of LOAD. The strategy is to feed male and female rabbits a long-term, low-dose cholesterol diet in Aim 1, a high-fat diet in Aim 2, and a diet high in both sugar and fat in Aim 3 to recreate LOAD-like pathology and study the effects of hypercholesterolemia, obesity, and hyperglycemia on learning and memory using a range of increasingly complex tasks – well-understood paradigms that are altered in LOAD patients and we have shown to be affected by dietary manipulations in rabbits. We will also assess the cellular and neuropathological effects of hypercholesterolemia, obesity, and hyperglycemia including their impact on the neurobiology of learning and memory. Compelling preliminary data provide evidence that a short-term, high-dose cholesterol diet, a high-fat diet, and chemically-induced diabetes have deleterious effects on a range of learning and memory tasks. Preliminary electrophysiological evidence shows that feeding a diet high in cholesterol or high in fat can impair a well-known form of synaptic plasticity thought to underlie learning and memory – long-term potentiation. Published and preliminary pathophysiological data show significant diet- induced changes in cellular and neuropathological markers of LOAD. Taken together, these data provide proof of concept, but the levels of hypercholesterolemia and hyperglycemia were high and, although they recapitulated LOAD-like pathologies including beta amyloid accumulation, they also produced off-target pathology. It is therefore important to establish, characterize, and validate the cognitive and pathophysiological effects of milder, more long-term dietary manipulations that induce the types and levels of hypercholesterolemia, obesity, and hyperglycemia that are more clinically relevant. Our expertise in and track record of inducing significant behavioral, electrophysiological, and pathophysiological changes by manipulating diets in adult rabbits makes us well-suited to develop, characterize, and validate these unconventional models of LOAD – models that may represent improved translational potential by better replicating the cellular, neuropathological, and cognitive features of LOAD than current rodent models.

摘要：尽管转基因小鼠模型对我们对阿尔茨海默氏症的理解做出了重大贡献 NIA疾病得出的结论是，这些模型可能是“人类临床试验中的预测价值差” [RFA- AG-21-003]。结果，需要使用新的，创新的，非腐烂的哺乳动物模型来更好 概括了晚期阿尔茨海默氏病（负载）的细胞，神经病理和认知标志。 这些应包括可以系统地诱导负载风险因素的模型，在其中 认知定义是可以评估负载最早的标志。有令人信服的流行病学 饮食和生活方式是认知功能的重要决定者的证据，但目前尚不清楚这种因素如何 随着高胆固醇，肥胖和糖尿病的高度增加，会增加认知缺陷的可能性。电流的目的 建议是开发，表征和验证非常规的哺乳动物模型，这些模型概括了 负载的细胞，神经病理学和认知标志。策略是喂男性和雌性兔子 AIM 1中的长期低剂量胆固醇饮食，AIM 2中的高脂饮食，AIM中的糖和脂肪含量高。 3重现类似负荷的病理并研究高胆固醇血症，肥胖和高血糖对 使用一系列越来越复杂的任务学习和记忆 - 被改变 在负载患者中，我们已证明会受到兔子饮食操纵的影响。我们还将评估 高胆固醇血症，肥胖和高血糖的细胞和神经病理学作用，包括其影响 关于学习和记忆的神经生物学。引人入胜的初步数据提供了短期的证据 高剂量胆固醇饮食，高脂饮食和化学诱发的糖尿病已删除了对范围的影响 学习和记忆任务。初步电生理学证据表明，喂食饮食高 胆固醇或高脂肪会损害一种众所周知的突触可塑性形式，认为是学习的基础 记忆 - 长期潜力。发表和初步的病理生理数据显示出明显的饮食 - 诱导的负载的细胞和神经病理学标志物的变化。综上所述，这些数据提供了证明 概念，但是高胆固醇血症和高血糖的水平很高，尽管它们概括了 类似负荷的病理包括β-淀粉样蛋白的积累，它们还产生了靶标病理。这是 因此，重要的是建立，表征和验证米勒的认知和病理生理影响， 更长期的饮食操纵影响高胆固醇血症，肥胖和 高血糖在临床上更相关。我们在引起诱发的大量的专家和记录 通过操纵成年兔子的饮食使行为，电生理和病理生理变化使 我们非常适合开发，表征和验证这些非常规的负载模型 - 可能 通过更好地复制细胞，神经病理和认知来代表改善的翻译潜力 负载的功能比当前的啮齿动物模型。