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.

项目摘要/摘要 稀有形式的阿尔茨海默氏病（FAD）是由终身，一般确定的 淀粉样β-蛋白质（Aß）生产的扰动，但绝大多数所谓的原因 零星的AD（SAD）病例的定义较差。该建议将使用最先进的鼠标 悲伤的模型以及几种高度创新的方法来解决关键的临时和空间方面 第一次悲伤的发病机理，对有效疗法的发展产生了关键的影响。 FAD归因于Aß产生的慢性扰动，但我们假设触发了SAD 通过清除Aß的损害，特别是由于Aß清除率中的短暂障碍。这个假设 与表明SAD的几个既定风险因素，例如脑部创伤，压力， 或睡眠不足，由于Aß清除率降低，导致脑Aß水平短暂或发作的增加。到 对这个新型机械假设进行建模，我们采用创新方法来暂时抑制Aß清除率，并 通过阻断Aß的血脑屏障转运或其蛋白水解降解，可逆地。因为我们的目标 为了定义SAD的触发因素，我们需要一个不会自行发展AD型病理学的动物模型 就像大多数AD鼠标模型一样。为此，我们将使用创新的新鼠标模型Appnl-f/haß 在内源鼠应用启动子的控制下，仅表达野生型人Aß的小鼠， 对于模拟SAD所需的最小遗传突变。正常人类，这个悲伤的鼠标模型 以年龄的方式发展人Aß的弥漫性沉积物，并形成非常最小的密集核 斑块仅在非常高级的年龄。彼此之间，这些小鼠是研究病理生理的理想选择 负责触发“正常”Aß沉积到SAD中病理类型的转化的机制。 我们进一步假设，与SAD最相关的Aß依赖性病理机制发生了很多 早于临床试验的年龄研究，临床符号仅在很久以后出现，特别是在 衰老的背景。彼此之间，我们将定义与AD出现最相关的临时窗口 在各个年龄段瞬时提高AppNL-F/Haß小鼠的Aß水平，然后评估对 纵向发展AD型病理学，直至和包括老年。 最后，我们将测试新颖的假设，即Aß（例如，额外的）撞击的空间不同的池 广告的发病机理在质上不同。具体而言，我们假设细胞内Aß更多 比细胞外Aß相关的与AD的神经变性和记忆丧失相关。为了测试这一点，我们 通过可逆地下调Aß降解蛋白酶，将有选择地增加Aß的外部与细胞内池 正如我们的初步结果所示，这有选择地调节Aß的这些不同的池。总的来说，这些 实验将使我们能够首次清洁和首次调查许多关键的临时和空间方面 在AD发病机理上，产生新的见解，可以为改进的SAD治疗方法提供帮助。