CONFERENCE ON NEURONAL AND VASCULAR STRESS

在阿尔茨海默病和脑血管淀粉样血管病中，淀粉样β-肽(Abeta)是细胞应激的致病因素，并最终对神经元和血管系统产生细胞毒性作用。尽管在阿尔茨海默病病程的晚期有大量致密的细胞外斑块样沉积，但很明显，在Abeta的生成和毒性过程中的更早事件，特别是在内质网内，将是充分了解Abeta的关键，以便设计在细胞功能障碍仍然可逆的阶段阻止疾病的治疗方法。Abeta的早老素、细胞表面和细胞内靶点的生物学聚集在小胶质细胞-神经元相互作用和血管系统上，创造了持续和破坏性炎症的环境，以及对缺血应激的夸大和不良反应。将描述来自新的动物模型和临床研究的见解，并与阿尔茨海默病和脑血管淀粉样血管病的一种新兴细胞生物学相关；即细胞功能障碍是由Abeta诱导的特定分子靶点的参与驱动的，而不是以前持有的由巨大的纤维非特异性和无情地破坏细胞膜的被动细胞破坏的概念。对阿尔茨海默病发病机制的这种改变的观点表明，未来的治疗干预措施有多个地点。

Recent findings have focused attention on amyloid beta-peptide (Abeta) as a key element in the pathogenicity of cell stress and, ultimately, cytotoxicity to neurons and the vasculature in Alzheimer's disease and cerebrovascular amyloid angiopathy. Although dense extracellular plaque-like deposits of Abeta are abundant late in the course of Alzheimer's disease, it has become evident that much earlier events in the generation and toxicity of Abeta, especially within the endoplasmic reticulum, will be critical to fully understand in order to design therapies that block the disease at a stage when cellular dysfunction is still reversible. Biology of the presenilins, cell surface and intracellular targets of Abeta converge on microglial-neuronal interactions and the vasculature to create a milieu of sustained and destructive inflammation, as well as an exaggerated and adverse response to ischemic stress. Insights from new animal models and clinical studies will be described, and related to an emerging cell biology of Alzheimer's disease and cerebrovascular amyloid angiopathy; namely, that of cellular dysfunction is driven by Abeta-induced engagement of specific molecular targets, rather than the previously held notion of passive cellular disruption by massive fibrils nonspecifically and inexorably destabilizing cell membranes. This altered view of the pathogenesis of Alzheimer's disease suggests multiple sites for future therapeutic interventions.