A novel APP-driven mechanism of neuroprotection in Alzheimer's disease

散发性阿尔茨海默病(AD)是最常见的痴呆症，没有治愈或有效的方法 治疗。绝大多数的治疗是基于淀粉样蛋白假说，该假说假设淀粉样蛋白Aβ 大脑中的堆积是引发疾病的关键因素。因此，这些疗法的重点是去除 过剩的Aβ，但不幸的是，它们未能产生临床改善。现在很明显，AD是一种 可能有几个致病因素的异质性疾病，这一事实阻碍了我们 对疾病的了解和循证治疗的设计。在这些因素中，胆固醇失调 是突出的，与至少20%的有患痴呆症风险的人口有关。这一特定的风险 人们将受益于我们对与胆固醇相关的潜在致病机制的了解 监管失调。在这方面，胆固醇失调参与AD的一个关键机制 发病机制是通过其氧化代谢产物27-羟基胆固醇(27OHC)的积累。我们的实验室 揭示了一种针对27OHC细胞毒性的新保护机制。我们已经证明，在体外， 淀粉样前体蛋白的胞内结构域AICD驱动神经保护性兴奋反应 27OHC通过上调氧化应激反应蛋白RTKN2来优化神经保护。这 AD患者的尸检脑样本和长期服用西药的小鼠的脑中存在反应缺陷 饮食，这是AD的一个重要危险因素，它会增加大脑中的27OHC。因此，我们的数据显示，AICD驱动的 对27OHC的兴奋作用在体外发生，并提示其激活可能与支持脑有关 动态平衡和维持认知功能。因此，我们的长期目标是理解钟表 在大脑中对抗27OHC的机制，以最终优化它们的治疗目的。整体而言 这一特定建议的目的是证明对27OHC的兴奋作用发生在大脑中作为一种 优化突触可塑性和认知功能的机制。在强劲数据的支持下，我们的核心假设是 通过27OHC的积累，增加对饮食中胆固醇的暴露，将导致 小鼠大脑中的兴奋反应窗口，可通过AICD驱动的RTKN2表达的变化来测量，海马区 突触可塑性和认知功能。我们将通过以下具体目标来检验我们的假设：测量 AICD诱导的小鼠海马区RTKN_2表达、突触可塑性及认知功能的变化 对饮食中胆固醇含量增加的反应。我们将使用类固醇27羟基酶缺失的小鼠，它确实 不产生27OHC，对照组，喂饲标准的或0.06%、0.125%、0.25%、0.375%和0.5%的胆固醇- 丰富饮食，以测量AICD驱动的RTKN2表达，评估器官型海马突触的可塑性 切片并评估广泛用于表征AD小鼠模型的一系列行为任务。我们的方法 是创新的，因为它描述了一种新的神经保护机制，以对抗AD的已知危险因素及其 贡献是巨大的，因为该机制的优化将提供循证治疗目标。

Sporadic Alzheimer’s disease (AD) is the most common form of dementia and it has no cure or effective treatment. The vast majority of therapies are based on the amyloid hypothesis, which postulates that amyloid Aβ accumulation in the brain is the key disease initiator. Accordingly, those therapies have focused on removing excess Aβ but, unfortunately, they have failed to produce clinical improvements. It is now evident that AD is a heterogeneous disease with likely several contributing pathogenic factors, a fact that hampers both our understanding of the disease and the design of evidence-based therapies. Of those factors, cholesterol dysregulation is prominent, being linked to at least 20% of the population at risk of developing dementia. This specific at-risk population would benefit from our understanding of the underlying pathogenic mechanisms linked to cholesterol dysregulation. In that respect, one key mechanism by which cholesterol dysregulation is involved in AD pathogenesis is through the accumulation of its oxidized metabolite 27-hydroxycholesterol (27OHC). Our laboratory has unveiled a novel protective mechanism against 27OHC cytotoxicity. We have shown that, in vitro, the intracellular domain of the amyloid precursor protein, AICD, drives a neuroprotective hormetic response against 27OHC through the upregulation of the oxysterol stress responder RTKN2 to optimize neuroprotection. This response was deficient in autopsy brain samples from AD patients and in brains of mice fed a long-term Western diet, a significant risk factor for AD that increases 27OHC in the brain. Thus, our data show that AICD-driven hormesis against 27OHC occurs in vitro and suggest that its activation could be implicated in supporting brain homeostasis and maintaining cognitive function. Accordingly, our long-term goal is to understand the hormetic mechanisms in the brain against 27OHC to ultimately optimize them for therapeutic purposes. The overall objective of this particular proposal is to demonstrate that hormesis against 27OHC occurs in the brain as a mechanism to optimize synaptic plasticity and cognitive function. Supported by strong data, our central hypothesis is that incremental exposure to dietary cholesterol, through the accumulation of 27OHC, will elicit a hormetic-response window in the mouse brain, measurable by changes in AICD-driven RTKN2 expression, hippocampal synaptic plasticity and cognitive function. We will test our hypothesis with the following Specific Aim: Measure the changes in AICD-driven RTKN2 expression, hippocampal synaptic plasticity and cognition in mice in response to increasing amounts of cholesterol in the diet. We will use sterol 27-hydroxylase-null mice, which do not generate 27OHC, and control mice, fed a standard or 0.06%, 0.125%, 0.25%, 0.375% and 0.5% cholesterol- rich diets, to measure AICD-driven RTKN2 expression, evaluate synaptic plasticity in organotypic hippocampal slices and assess a range of behavioral tasks widely used to characterize mouse models of AD. Our approach is innovative because it describes a novel neuroprotective mechanism against a known risk factor for AD and its contribution is significant because optimization of that mechanism will provide evidence-based therapy targets.