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

一种新的APP驱动的阿尔茨海默病神经保护机制

• 批准号: 10560408
• 负责人: Salvador Soriano
• 金额: $ 4.79万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10560408
• 关键词: 27-hydroxycholesterol; Affect; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autopsy; Behavioral; Biological Assay; Brain; Cholesterol; Cholesterol Homeostasis; Clinical; Cognition; Complement; Data; Dementia; Deposition; Development; Diet; Dietary Cholesterol; Disease; Dose; Exposure to; Family; Financial cost; Genetic; Genetic Risk; Goals; Hippocampus (Brain); Homeostasis; Impaired cognition; In Vitro; Knockout Mice; Knowledge; Laboratories; Link; Measurable; Measures; Mediating; Mission; Mixed Function Oxygenases; Mus; Nerve Degeneration; Outcome; Oxides; Pathogenesis; Pathogenicity; Pathway interactions; Play; Population; Population Attributable Risks; Populations at Risk; Positioning Attribute; Public Health; Reagent; Research; Role; Sampling; Signaling Protein; Slice; Sterols; Stress; Synaptic plasticity; Testing; Therapeutic; Transcriptional Activation; United States National Institutes of Health; Up-Regulation; Virulence Factors; Work; abeta accumulation; base; cognitive function; cost; cytotoxicity; design; effective therapy; evidence base; hypercholesterolemia; in vivo; innovation; mouse model; neuron loss; neuroprotection; novel; novel strategies; response; risk variant; societal costs; targeted treatment; therapeutic target; western diet; β-amyloid burden

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.

散发性阿尔茨海默病（AD）是最常见的痴呆形式，它没有治愈或有效 治疗绝大多数治疗方法都是基于淀粉样蛋白假说，即淀粉样蛋白Aβ 在大脑中的积累是主要的疾病引发剂。因此，这些疗法集中于去除 但不幸的是，它们未能产生临床改善。现在很明显，AD是一个 异质性疾病可能有几个致病因素，这一事实阻碍了我们的研究。 对疾病的理解和循证治疗的设计。在这些因素中，胆固醇失调 是一个突出的问题，与至少20%有患痴呆症风险的人口有关。这种特定的风险 人们将受益于我们对胆固醇相关的潜在致病机制的理解 失调在这方面，胆固醇失调的一个关键机制涉及AD 发病机制是通过其氧化代谢物27-羟基胆固醇（27 OHC）的积累。本实验室 已经揭示了一种新的保护机制，对27 OHC细胞毒性。我们已经证明，在体外， 淀粉样前体蛋白AICD的胞内结构域驱动神经保护性激素反应， 27 OHC通过上调氧固醇应激反应RTKN 2来优化神经保护。这 在AD患者的尸检脑样本和长期喂食Western blot的小鼠脑中， 饮食是AD的一个重要危险因素，可增加大脑中的27 OHC。因此，我们的数据显示， 在体外对27 OHC产生兴奋效应，表明其激活可能与支持脑 自我平衡和维持认知功能。因此，我们的长期目标是了解 在大脑中对抗27 OHC的机制，以最终优化它们用于治疗目的。整体 这一特殊建议的目的是证明，对27 OHC的兴奋效应发生在大脑中， 优化突触可塑性和认知功能的机制。在强有力的数据支持下，我们的中心假设是 通过27 OHC的积累，增加暴露于膳食胆固醇， 小鼠脑中的激素反应窗口，可通过AICD驱动的RTKN 2表达的变化来测量，海马 突触可塑性和认知功能。我们将用以下具体目标来检验我们的假设： AICD驱动的RTKN 2表达、海马突触可塑性和小鼠认知的变化， 对饮食中胆固醇含量增加的反应。我们将使用甾醇27-羟化酶缺失的小鼠， 不产生27 OHC，对照组小鼠分别饲喂标准或0.06%、0.125%、0.25%、0.375%和0.5%胆固醇。 丰富的饮食，以测量AICD驱动的RTKN 2表达，评估器官型海马中的突触可塑性， 切片和评估广泛用于表征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，针对已知的AD风险因素， 这一贡献是重要的，因为该机制的优化将提供基于证据的治疗靶点。

项目成果

Loss of APP in mice increases thigmotaxis and is associated with elevated brain expression of IL-13 and IP-10/CXCL10.

• DOI: 10.1016/j.physbeh.2021.113533
• 发表时间: 2021-10-15
• 期刊: PHYSIOLOGY & BEHAVIOR
• 影响因子: 2.9
• 作者: Mayagoitia, Karina;Tolan, Andrew J.;Shammi, Shohali;Shin, Samuel D.;Menchaca, Jesus A.;Figueroa, Johnny D.;Wilson, Christopher G.;Bellinger, Denise L.;Ahmed, Abu Shufian Ishtiaq;Soriano, Salvador
• 通讯作者: Soriano, Salvador