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了解阿尔茨海默病做出了重大贡献 NIA 得出的结论是，这些模型可能“在人体临床试验中预测价值较差”[RFA- AG-21-003]。因此，需要新的、创新的、非啮齿动物、哺乳动物模型来更好地 概括了迟发性阿尔茨海默病 (LOAD) 的细胞、神经病理学和认知特征。 这些应包括可以系统地诱导 LOAD 风险因素的模型，以及其中 可以评估作为 LOAD 最早标志的认知缺陷。有令人信服的流行病学证据 有证据表明饮食和生活方式是认知功能的重要决定因素，但尚不清楚这些因素如何影响认知功能。 因为高胆固醇、肥胖和糖尿病会增加认知缺陷的可能性。当前的目的 提议是开发、表征和验证非常规的哺乳动物模型，这些模型概括了 LOAD 的细胞、神经病理学和认知特征。策略是给雄性和雌性兔子喂食 目标 1 为长期低剂量胆固醇饮食，目标 2 为高脂肪饮食，目标 2 为高糖高脂肪饮食 3 重现 LOAD 样病理学并研究高胆固醇血症、肥胖和高血糖对 使用一系列日益复杂的任务进行学习和记忆——众所周知的范式发生了变化 在 LOAD 患者中，我们已经证明它受到兔子饮食控制的影响。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影响，包括其影响 学习和记忆的神经生物学。令人信服的初步数据提供了短期、 高剂量胆固醇饮食、高脂肪饮食和化学诱发的糖尿病对一系列疾病都有有害影响 学习和记忆任务。初步电生理学证据表明，饮食中富含 胆固醇或高脂肪会损害一种众所周知的突触可塑性，这种可塑性被认为是学习和学习的基础。 记忆——长时程增强。已发表的和初步的病理生理学数据显示显着的饮食- 诱导 LOAD 的细胞和神经病理学标志物的变化。综合起来，这些数据提供了证据 的概念，但高胆固醇血症和高血糖水平很高，尽管它们概括了 类似 LOAD 的病理包括 β 淀粉样蛋白积累，它们也会产生脱靶病理。这是 因此，确定、表征和验证较温和的认知和病理生理学影响非常重要， 更长期的饮食控制会导致高胆固醇血症、肥胖和高胆固醇血症的类型和水平 与临床更相关的高血糖。我们在诱导重大事件方面的专业知识和记录 通过控制成年兔子的饮食来观察行为、电生理和病理生理变化 我们非常适合开发、表征和验证这些非传统的 LOAD 模型——这些模型可能 通过更好地复制细胞、神经病理学和认知能力，代表了转化潜力的提高 LOAD 与当前啮齿动物模型相比的特点。