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

翻译后摘要：尽管转基因小鼠模型的重大贡献，我们对阿尔茨海默氏症的理解， 疾病，NIA得出结论，这些模型可能“在人类临床试验中的预测价值较差”[RFA- AG-21-003]。因此，需要新的、创新的、非啮齿动物的哺乳动物模型，其更好地 概括了迟发性阿尔茨海默病（LOAD）的细胞、神经病理和认知特征。 这些模型应该包括可以系统地诱导负载风险因素的模型，并且其中 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 有证据表明，饮食和生活方式是认知功能的重要决定因素，但目前还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 建议是开发，表征和验证非常规的哺乳动物模型，以概括 LOAD的细胞、神经病理和认知特征。策略是给雄兔和雌兔喂食 Aim 1中长期低剂量胆固醇饮食，Aim 2中高脂肪饮食，Aim中高糖和高脂肪饮食 3重建LOAD样病理学并研究高胆固醇血症、肥胖和高血糖对 学习和记忆使用一系列日益复杂的任务-众所周知的范式， 在LOAD患者中，我们已经证明了饮食操作对兔子的影响。我们亦会评估 高胆固醇血症、肥胖症和高血糖症的细胞和神经病理学效应，包括其影响 关于学习和记忆的神经生物学。令人信服的初步数据提供了证据， 高剂量胆固醇饮食、高脂肪饮食和化学诱导的糖尿病会对一系列人产生有害影响 学习和记忆任务。初步的电生理学证据表明，喂食高浓度的饮食， 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， 导致LOAD的细胞和神经病理学标志物的变化。综合起来，这些数据证明 概念，但高胆固醇血症和高血糖症的水平很高，虽然他们概括 LOAD样病理包括β淀粉样蛋白积聚，它们也产生脱靶病理。是 因此，重要的是建立、表征和验证较轻， 更长期的饮食操纵会诱发高胆固醇血症、肥胖和高胆固醇血症的类型和水平 与临床相关性更高的高血糖症。我们的专业知识和跟踪记录， 行为，电生理和病理生理变化，通过操纵成年兔的饮食， 我们非常适合开发，表征和验证这些非常规的LOAD模型-模型可以 通过更好地复制细胞、神经病理学和认知功能， LOAD的功能比目前的啮齿动物模型。

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.