Zhong Ning, Weisgraber Karl H
The Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
Curr Alzheimer Res. 2009 Oct;6(5):415-8. doi: 10.2174/156720509789207921.
Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD) by an as yet to be defined mechanism. Since the structure or biophysical properties of a protein directly determines function, our approach to addressing mechanism is structure:function based. Domain interaction a structural property of apoE4 that distinguishes it from apoE3 is predicted to contribute to the association of apoE4 with AD. We developed a mouse model, the Arg-61 apoE model, which is specific for domain interaction. These mice display synaptic, functional, and cognitive deficits, demonstrating domain interaction is the causative factor. We present evidence that domain interaction results in stressed astrocytes that are dysfunctional and propose that dysfunctional astrocytes are an early player in apoE4-associated AD and that domain interaction is a potential therapeutic target.
载脂蛋白E4（apoE4）是阿尔茨海默病（AD）的主要遗传风险因素，但其机制尚未明确。由于蛋白质的结构或生物物理特性直接决定其功能，我们研究机制的方法是基于结构与功能的关系。结构域相互作用是apoE4区别于apoE3的一种结构特性，预计它与apoE4和AD的关联有关。我们构建了一种小鼠模型，即精氨酸-61 apoE模型，该模型对结构域相互作用具有特异性。这些小鼠表现出突触、功能和认知缺陷，表明结构域相互作用是致病因素。我们提供的证据表明，结构域相互作用会导致星形胶质细胞应激并功能失调，并提出功能失调的星形胶质细胞是apoE4相关AD的早期参与者，且结构域相互作用是一个潜在的治疗靶点。
