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.

零星的阿尔茨海默氏病（AD）是痴呆症的最常见形式，没有治愈或有效 治疗。绝大多数疗法基于淀粉样假说，该假设假设淀粉样蛋白Aβ 大脑中的积累是关键疾病引发剂。彼此之间，这些疗法的重点是去除 过多的Aβ，但不幸的是，它们未能产生临床改善。现在有证据表明广告是 异质性疾病可能有几种导致的致病因素，这一事实使我们的两者都受阻 了解该疾病和循证疗法的设计。在这些因素中，胆固醇失调 很突出，与至少20％的人口有痴呆症的风险有关。这种特定的高风险 人口将受益于我们对与胆固醇相关的潜在致病机制的理解 失调。在这方面，胆固醇失调参与AD的一种关键机制 发病机理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 已经公布了一种针对27OHC细胞毒性的新型保护机制。我们已经表明，在体外 淀粉样蛋白前体蛋白的细胞内结构域AICD驱动针对神经保护性的Hommetic反应 27OHC通过上调氧酚应力响应者RTKN2以优化神经保护作用。这 反应不足于AD患者的尸检脑样品和喂养长期西部的小鼠的大脑 饮食是AD的重要危险因素，它增加了大脑中的27OHC。这，我们的数据表明AICD驱动 针对27OHC的激素发生在体外发生，并表明其激活可以暗示在支撑大脑中 稳态和维持认知功能。据认为，我们的长期目标是理解Hommetic 针对27OHC的大脑机制最终将其优化为治疗目的。总体 该特定提议的目的是证明27OHC在大脑中作为一个 优化合成可塑性和认知功能的机制。在强大数据的支持下，我们的中心假设是 通过积累27OHC的饮食胆固醇的增量暴露将引起 小鼠大脑中的Hommetic-Respons窗口，可通过AICD驱动的RTKN2表达，海马的变化来测量 突触可塑性和认知功能。我们将以以下特定目的检验我们的假设：测量 小鼠的AICD驱动的RTKN2表达，海马突触可塑性和认知的变化 对饮食中胆固醇量增加的反应。我们将使用固醇27-羟化酶无效的小鼠， 未产生27OHC，并对照小鼠喂养标准或0.06％，0.125％，0.25％，0.375％和0.5％胆固醇 - 丰富的饮食，测量AICD驱动的RTKN2表达，评估有机海马中的合成可塑性 切片并评估广泛用于表征AD鼠标模型的一系列行为任务。我们的方法 具有创新性，因为它描述了一种针对已知的AD危险因素的新型神经保护机制 贡献很重要，因为该机制的优化将提供循证治疗靶标。

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