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 罕见的家族性阿尔茨海默病(FAD)已知是由终生的、由基因决定的 摄动产生的淀粉样蛋白(A？)，但其起因(S)绝大多数所谓 散发性阿尔茨海默病(SAD)病例的定义仍然非常模糊。这项提案将使用最先进的鼠标 可持续发展战略的模型以及几种高度创新的方法来解决关键的时间和空间问题 第一次发现了悲伤的发病机制，这对有效治疗的发展具有重要意义。 虽然FAD可归因于Aü的产生的长期扰动，但我们假设Sad被触发 A？这一假设 与证据一致的证据表明，几个确定的危险因素，如脑创伤，压力， 或睡眠不佳，导致短暂的或间歇性的脑Aü水平增加，这是由于A？清除量降低。至 建立这一新的机制假说的模型，我们使用创新的方法来瞬时抑制A？清除和 可逆地通过阻断血脑屏障转运或其蛋白分解降解。因为我们的目标是 为了定义SAD的触发因素，我们需要一个本身不会发展为AD类型的病理的动物模型， 就像大多数AD小鼠模型一样。为此，我们将使用一种创新的新的SAD小鼠模型，APPNL-F/ha？ 只表达野生型人类A？的小鼠，在内源性小鼠App启动子的控制下， 只需最小的基因突变就可以建立SAD模型。就像普通人一样，这个悲伤的小鼠模型 以与年龄相关的方式形成人的弥漫沉积，并形成非常小的致密核 斑块只有在年龄很大的时候才会出现。因此，这些小鼠是研究病理生理学的理想动物。 触发SAD“正常”沉积向病理性转化的机制。 我们进一步假设，与SAD最相关的依赖于A？的病理机制 比临床试验中研究的年龄更早，临床症状出现得更晚，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的出现最相关的时间窗口 在不同年龄的APPNL-F/haü小鼠中短暂增加Aü水平，然后评估对 纵向发展的AD类型的病理，直到并包括老年。 最后，我们将测试空间上不同的A？池(例如，胞外和胞内)影响的新假设 阿尔茨海默病的发病机制有质的不同。具体地说，我们假设细胞内的A？ 而不是细胞外Aü与阿尔茨海默病的神经退行性变和记忆力丧失有关。为了测试这一点，我们 将通过可逆地下调A？降解酶来选择性地增加A？的胞外池和胞内池。 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A？池。总而言之，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 对AD发病机制的研究，产生了新的见解，将为改进治疗SAD的方法提供信息。