Role of circulating Abeta seeds and peripheral tissue damage in Alzheimer's disease pathogenesis

首席调查员/项目主任(最后、第一、中间)：索托、克劳迪奥/莫拉莱斯、罗德里戈 摘要 一些使用阿尔茨海默病(AD)动物模型的报告表明，淀粉样β蛋白(Aβ)和tau 聚集体可以扩散到不同的组织，促进观察到的典型脑损伤的出现。 在这种疾病中。血液和外周清除在这些结构扩散中的作用尚未得到 广泛探索。我们的初步结果表明，具有生物活性的Aβ寡聚种子存在于 AD患者和动物模型的血液，提示这种生物液体可能在AD的 疾病的传播。通过静脉注射Aβ聚集体来支持这一数据 加速转基因小鼠脑淀粉样变性及全血清除循环Aβ聚集体 Exchange显著减少了大脑淀粉样蛋白的沉淀量。我们的工作假设是血液 有助于生物活性Aβ寡聚种子的传播和外周清除的损害 阿尔茨海默病的发病机制对AD的病因和进展具有重要意义。我们亦建议， 血液中功能性Aβ寡聚体的存在可能使开发新的诊断和治疗策略成为可能 A-β聚集物外周池的治疗。为了检验这一假设，我们计划确定和 使用新的体外技术和技术表征AD患者血液中具有生物学功能的Aβ聚集体 动物模型。此外，我们还将探讨急性或慢性肝脏对外周Aβ清除的异常 损伤影响家族性和散发性AD模型中淀粉样蛋白沉积的进展。此外，我们还将 通过尝试开发新的诊断和诊断策略来研究这些发现的翻译含义 基于错误折叠的Aβ聚合体存在于血液中并与病理有关的治疗 在大脑里。在诊断方面，我们建议改用Aβ，一种超灵敏的蛋白质检测方法 在血液中聚集。这种名为PMCA的测试最初是由我们实验室开发的，用于检测普恩病毒，并已 已被广泛用于鉴定患者血液中的病理性病毒。在治疗方面，我们建议 进行概念验证研究，以分析从血液中去除Aβ聚集体对 大脑的病理和功能异常。清除活体动物体内循环中的Aβ聚集体将 通过血浆置换和血液透析来完成。这个项目中提出的实验将使我们能够研究 一种被广泛认为是最早的病理疾病发生和发展的可能机制 阿尔茨海默病的改变，即Aβ的错误折叠、聚集和脑积聚。

Principal Investigator/Program Director (Last, first, middle): Soto, Claudio / Morales, Rodrigo ABSTRACT Several reports using animal models of Alzheimer's disease (AD) suggest that amyloid-beta (Aβ) and tau aggregates can spread across different tissues promoting the appearance of the typical brain lesions observed in this disease. The role of blood and peripheral clearance in the spread of these structures has not been extensively explored. Our preliminary results show that biologically active Aβ oligomeric seeds are present in blood of AD patients and animal models, suggesting that this biological fluid may play an important role in the spreading of the disease. Supporting this data, administration of Aβ aggregates by intra-venous injection accelerates brain amyloidosis in transgenic mice and removal of circulating Aβ aggregates by whole blood exchange dramatically reduces the amount of cerebral amyloid deposits. Our working hypothesis is that blood contributes to the spread of biologically active Aβ oligomeric seeds and that impairment in peripheral clearance mechanisms has significant implications for the etiology and progression of AD. We also propose that the presence of functional Aβ oligomers in blood may enable the development of novel strategies for diagnosis and therapy focusing on the peripheral pool of Aβ aggregates. To test this hypothesis we plan to identify and characterize biologically functional Aβ aggregates in blood of AD patients, using novel in vitro techniques and animal models. Also, we will explore whether abnormalities on peripheral Aβ clearance by acute or chronic liver damage affects the progression of amyloid deposition in models of familial and sporadic AD. Moreover, we will study the translational implication of these findings by attempting to develop novel strategies for diagnosis and treatment based on the idea that misfolded Aβ aggregates are present in blood and contribute to the pathology in the brain. In the diagnostic side, we propose to adapt to Aβ an assay for ultra-sensitive detection of protein aggregates in blood. This assay, termed PMCA, was originally developed in our lab to detect prions and has been widely utilized to identify pathological prions in blood of patients. In the therapeutic side, we propose to perform proof-of-concept studies to analyze the benefit of removing Aβ aggregates from the blood for the pathological and functional abnormalities in the brain. Removal of circulating Aβ aggregates in live animals will be done by plasmapheresis and blood dialysis. The experiments proposed in this project will enable to investigate a possible mechanism for the initiation and progression of what is widely considered as the earliest pathological alteration in AD, i.e. the misfolding, aggregation and cerebral accumulation of Aβ.