The Mechanisms Of The Cellular Phase Of Alzheimer's Disease

阿尔茨海默病（AD）仍然是最大的未满足的医疗需求的领域之一。AD是一个缓慢的过程，在几十年内不断发展，在临床症状出现之前有一个很长的前驱期。这一点，再加上散发性AD的复杂遗传结构，使得有必要修改AD发病机制的简化模型。我们定义了“AD的细胞阶段”的概念，讨论了大脑中所有类型的细胞如何对淀粉样蛋白病理学做出反应，但仍能维持大脑长时间的稳态。只有在疾病的最后阶段，大脑功能性崩溃才会引起临床阶段。此外，散发性AD的高遗传率（58-79%）表明遗传风险是这些细胞反应的重要决定因素。AD遗传风险的很大一部分是在神经元以外的细胞中表达的基因，这强化了细胞阶段对于理解AD向痴呆的进展至关重要的概念。在目前的项目中，我们专注于我们的嵌合小鼠模型，以及它们如何用于捕获人类细胞疾病模型中的多基因风险，目的是了解机制。这项工作的总体目标是为AD提供细胞理论，并确定病理过程中的关键步骤。与目前专注于阻断AD生化标志出现或试图治疗终末期痴呆症的疗法相比（Long和Holtzman 2019），利用AD自然恢复机制的疗法有望成为一种新的，可能更有效的治愈途径。

Alzheimer's disease (AD) remains one of the areas of greatest unmet medical need. AD is a slow process evolving over decades, with a long prodromal phase before clinical symptoms appear. This, together with the complex genetic architecture of sporadic AD, made it necessary to revise the reductionist models for AD pathogenesis. We defined the concept of "the cellular phase of AD", discussing how all cell types of the brain react to amyloid pathology yet maintain the brain for a long time in homeostasis. It is only in the end phase of the disease that the brain functionally collapses giving rise to the clinical phase. In addition, the high heritability (58-79%) of sporadic AD suggests that genetic risk is an important determinant of these cellular reactions. A large part of genetic risk of AD is in genes that are expressed in cells other than neurons, reinforcing the concept that the cellular phase is crucial to understand the progression of AD towards dementia. In the current project we focus on our chimeric mouse models and how they can be used to capture polygenic risk in human cellular models of disease with the aim of understanding mechanisms. The overall aim of the work is to provide a cellular theory for AD and to identify critical steps in the pathological process. In contrast to current therapies that focus on blocking the appearance of the biochemical hallmarks of AD or attempting to treat end-stage dementia (Long and Holtzman 2019), therapies that engage the natural resilience mechanisms of AD promise a new and possibly more effective path to a cure.