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

摘要：尽管转基因小鼠模型对我们了解阿尔茨海默氏症做出了重大贡献 NIA得出的结论是，这些模型在人类临床试验中的预测价值可能很差。 AG-21-003]。因此，需要新的、创新的、非啮齿动物的、能够更好地 概述迟发性阿尔茨海默病(LOAD)的细胞、神经病理和认知特征。 这些模型应包括可系统地归纳负荷风险因素的模型，以及 作为负荷的最早标志的认知缺陷是可以评估的。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是如何决定的 因为高胆固醇、肥胖和糖尿病会增加认知障碍的可能性。当前的目的是 建议是开发、表征和验证非传统的哺乳动物模型，这些模型概括了 负荷的细胞、神经病理和认知特征。其策略是给公兔和母兔喂食一次 AIM 1组长期低剂量胆固醇饮食，AIM 2组高脂肪饮食，AIM组高糖高脂饮食 3重建负荷性病理，研究高胆固醇血症、肥胖和高血糖对血管内皮生长的影响。 使用一系列日益复杂的任务进行学习和记忆--被改变的众所周知的范例 在LOAD患者中，我们已经证明在兔子身上受到饮食控制的影响。我们亦会评估 高胆固醇血症、肥胖和高血糖的细胞和神经病理效应，包括它们的影响 关于学习和记忆的神经生物学。令人信服的初步数据证明，短期内， 高剂量胆固醇饮食、高脂肪饮食和化学诱导的糖尿病对一系列疾病都有有害影响。 学习和记忆任务。初步的电生理证据表明，喂食高热量的食物 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 记忆--长时程增强。已发表的和初步的病理生理数据显示，重要的饮食- 诱导负荷的细胞和神经病理标志物的变化。总而言之，这些数据提供了证据 概念，但高胆固醇血症和高血糖水平很高，尽管它们概括起来 负荷样病理包括β淀粉样堆积，它们也产生偏离靶点的病理。它是 因此，重要的是建立、表征和验证MERDER的认知和病理生理效应， 更长期的饮食控制会导致高胆固醇血症、肥胖和 临床上更相关的高血糖。我们在以下方面的专业知识和记录： 操纵饲料对成年兔的行为、电生理和病理生理学的影响 美国非常适合开发、表征和验证这些非传统的负载模型-这些模型可以 通过更好地复制细胞、神经病理和认知功能来提高翻译潜力 载荷特征比目前的啮齿动物模型要好。

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.