Chen S, Frederickson R C, Brunden K R
Gliatech Incorporated, Cleveland, OH 44122, USA.
Neurobiol Aging. 1996 Sep-Oct;17(5):781-7. doi: 10.1016/0197-4580(96)00103-0.
Increasing evidence points to A beta-containing senile plaques as primary etiological agents in Alzheimer's disease (AD). The mechanism by which these deposits cause neurotoxicity is unresolved, but there are compelling data suggesting that the activated glia found associated with senile plaques contribute to the pathology of AD. These cells appear to release a variety of immunoinflammatory molecules, including complement proteins whose activation products colocalize with senile plaques and dystrophic neurites. Previous studies showed that A beta can bind and activate complement protein C1q, providing a plausible explanation for the initiation of the complement cascade in AD. Data presented here further define the nature of A beta-C1q association, revealing key aspects of the C1q domain involved in binding the amyloid peptide. Moreover, we show that it is possible to inhibit A beta-induced complement activation without affecting the normal immunoglobulin-mediated complement pathway. This indicates that it should be feasible to develop drugs to reduce complement damage in AD without compromising this important immune-defense mechanism throughout the body.
越来越多的证据表明，含有β淀粉样蛋白的老年斑是阿尔茨海默病（AD）的主要病因。这些沉积物导致神经毒性的机制尚未明确，但有令人信服的数据表明，与老年斑相关的活化胶质细胞促成了AD的病理过程。这些细胞似乎会释放多种免疫炎症分子，包括补体蛋白，其激活产物与老年斑和营养不良性神经突共定位。先前的研究表明，β淀粉样蛋白可以结合并激活补体蛋白C1q，为AD中补体级联反应的启动提供了一个合理的解释。此处呈现的数据进一步明确了β淀粉样蛋白与C1q结合的性质，揭示了C1q结构域中与淀粉样肽结合相关的关键方面。此外，我们表明有可能在不影响正常免疫球蛋白介导的补体途径的情况下抑制β淀粉样蛋白诱导的补体激活。这表明开发药物以减少AD中的补体损伤而不损害全身这一重要的免疫防御机制应该是可行的。
