The Mechanisms Of The Cellular Phase Of Alzheimer's Disease

阿尔茨海默病(AD)仍然是最大的未得到满足的医疗需求领域之一。AD是一个经过几十年演变的缓慢过程，在临床症状出现之前有一个很长的前驱阶段。这一点，再加上散发性AD复杂的遗传结构，使得修订AD发病机制的简化论模型是必要的。我们定义了“阿尔茨海默病的细胞期”的概念，讨论了大脑的所有细胞类型如何对淀粉样蛋白病理做出反应，同时又能在很长一段时间内维持大脑的稳态。只有在疾病的末期，大脑才会出现功能性崩溃，从而导致临床期。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的很大一部分遗传风险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，我们将重点放在我们的嵌合小鼠模型上，以及如何使用它们来捕获人类疾病细胞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阿尔茨海默病提供细胞理论，并确定病理过程中的关键步骤。与目前专注于阻止AD生化特征的出现或试图治疗终末期痴呆症(Long和Holtzman 2019)的疗法不同，利用AD的自然弹性机制的疗法有望提供一条新的、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.