Temporal and spatial aspects of amyloidogenesis in sporadic Alzheimer disease

散发性阿尔茨海默病淀粉样蛋白生成的时间和空间方面

• 批准号: 10475279
• 负责人: MALCOLM A LEISSRING
• 金额: $ 54.31万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475279
• 关键词: ABCB1 gene; Abeta clearance; Abeta synthesis; Address; Age; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Aspartic Endopeptidases; Basic Science; Blood - brain barrier anatomy; Brain; Cathepsins; Cells; Cerebrum; Chronic; Clinical; Clinical Trials; DNA Sequence Alteration; Data; Defect; Deposition; Development; Diffuse; Disease; Down-Regulation; Early Diagnosis; Elderly; Environment; Etiology; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Genetic; Goals; Grant; Human; Impairment; Innovative Therapy; Knock-in Mouse; Lead; Life; Link; Memory Loss; Methods; Modeling; Mus; Mutation; Neprilysin; Nerve Degeneration; Neuronal Dysfunction; Neurons; Pathogenesis; Pathologic; Pathology; Peptide Hydrolases; Play; Proteins; Risk Factors; Role; Senile Plaques; Stress; Study models; Symptoms; Tariquidar; Testing; Time; Traumatic Brain Injury; Twin Multiple Birth; Work; abeta deposition; age related; aged; amyloidogenesis; effective therapy; experimental study; extracellular; familial Alzheimer disease; human old age (65+); improved; inhibitor; innovation; insight; interest; mouse model; novel; poor sleep; promoter; therapeutically effective

PROJECT SUMMARY/ABSTRACT Rare forms of familial Alzheimer disease (fAD) are known to be caused by life-long, genetically determined perturbations in the production of the amyloid ß-protein (Aß), but the cause(s) of the vast majority of so-called sporadic AD (sAD) cases remains remarkably poorly defined. This proposal will use state-of-the-art mouse models of sAD together with several highly innovative approaches to address key temporal and spatial aspects of sAD pathogenesis for the first time, with critical implications for the development of effective therapies. Whereas fAD is attributable to chronic perturbations in the production of Aß, we hypothesize that sAD is triggered by impairments in the clearance of Aß—specifically by transient impairments in Aß clearance. This hypothesis is consistent with evidence showing that several established risk factors for sAD, such as brain trauma, stress, or poor sleep, lead to short-lived or episodic increases in cerebral Aß levels due to reduced Aß clearance. To model this novel mechanistic hypothesis, we employ innovative methods to inhibit Aß clearance transiently and reversibly by blocking either blood-brain barrier transport of Aß or its proteolytic degradation. Because we aim to define the triggers for sAD, we require an animal model that does not develop AD-type pathology on its own, as most AD mouse models do. To this end, we will use an innovative new sAD mouse model, the APPNL-F/hAß mice, which expresses wild-type human Aß only, under the control of the endogenous murine App promoter, with the minimal genetic mutations needed to model sAD. As is true for normal humans, this sAD mouse model develops diffuse deposits of human Aß in an age-dependent manner, and forms very minimal dense-core plaques only at very advanced ages. Accordingly, these mice are ideal for investigating the pathophysiological mechanisms responsible for triggering the conversion of “normal” Aß deposition to the pathological type in sAD. We hypothesize further that the Aß-dependent pathological mechanisms most relevant to sAD occur much earlier than the ages studied in clinical trials, with clinical symptoms emerging only much later, specifically in the context of aging. Accordingly, we will define the temporal window most relevant to the emergence of AD by increasing Aß levels in APPNL-F/hAß mice transiently at various ages, then evaluating the consequences for the development of AD-type pathology longitudinally, up to and including old age. Finally, we will test the novel hypothesize that spatially distinct pools of Aß (e.g., extra- vs. intracellular) impact the pathogenesis of AD in qualitatively different ways. Specifically, we postulate that intracellular Aß is more relevant than extracellular Aß to the neurodegeneration and memory loss that characterize AD. To test this, we will selectively increase extra- vs. intracellular pools of Aß by reversibly downregulating Aß-degrading proteases that, as our preliminary results show, selectively regulate these distinct pools of Aß. Collectively, these experiments will allow us to investigate, cleanly and for the first time, many critical temporal and spatial aspects of AD pathogenesis, yielding novel insights that will inform improved approaches to the treatment of sAD.

项目总结/摘要 已知罕见的家族性阿尔茨海默病（fAD）是由终身遗传决定的， 淀粉样β-蛋白（AAPs）的产生扰动，但绝大多数所谓的 散发性AD（sAD）病例的定义仍然非常差。本提案将使用最先进的鼠标 可持续农业发展模型以及若干高度创新的方法，以解决关键的时间和空间问题 sAD发病机制的首次，具有重要意义的发展，有效的治疗方法。 而fAD是由于慢性扰动生产的AALGOT，我们假设，sAD是触发 通过Ablast清除障碍-特别是通过Ablast清除的短暂障碍。这一假设 与证据显示的几个确定的sAD风险因素，如脑外伤，压力， 或睡眠不佳，由于减少的Ablation清除率，导致脑Ablation水平的短暂或间歇性增加。到 模型这种新的机制假设，我们采用创新的方法来抑制Ablation清除短暂， 可逆地通过阻断血脑屏障转运或其蛋白水解降解。因为我们的目标是 为了确定sAD的触发因素，我们需要一种动物模型，其自身不会发展成AD型病理， 与大多数AD小鼠模型一样。为此，我们将使用一种创新的新型sAD小鼠模型，APPNL-F/hAD小鼠模型， 在内源性鼠App启动子控制下，仅表达野生型人App的小鼠， 用最小的基因突变来模拟sAD与正常人一样，这种sAD小鼠模型 以年龄依赖性方式发展人类A12的弥漫性沉积，并形成非常小的致密核心 只有在非常高的年龄斑块。因此，这些小鼠是研究病理生理学的理想小鼠。 负责触发sAD中“正常”Ablast沉积转化为病理类型的机制。 我们进一步假设，与sAD最相关的依赖于腺苷酸的病理机制发生得更频繁， 早于临床试验中研究的年龄，临床症状只出现得更晚，特别是在 老龄化的背景。因此，我们将通过以下方式定义与AD出现最相关的时间窗口： 在不同年龄短暂增加APPNL-F/hA β小鼠中的A β水平，然后评估 AD型病理的纵向发展，直至并包括老年。 最后，我们将测试新的假设，即空间上不同的Abladium池（例如，细胞外与细胞内）影响 AD的发病机制有质的不同。具体地说，我们假设细胞内的腺苷酸更多地是 与细胞外腺苷酸相比，它与AD的特征性神经变性和记忆丧失有关。为了验证这个，我们 将通过可逆地下调腺苷酸降解蛋白酶，选择性地增加腺苷酸的细胞外和细胞内库 正如我们的初步结果所显示的那样，它选择性地调节这些不同的Ablation池。总的来说，这些 实验将使我们能够第一次干净地调查许多关键的时间和空间方面 AD发病机制，产生新的见解，将通知改善方法治疗sAD。