CONFERENCE ON NEURONAL AND VASCULAR STRESS

最近的研究结果集中在淀粉样蛋白β肽（Abeta）作为细胞应激致病性的关键因素，并最终在阿尔茨海默病和脑血管淀粉样血管病中对神经元和脉管系统产生细胞毒性。尽管在阿尔茨海默病的晚期，密集的细胞外斑块样沉积物丰富，但很明显，在Abeta的产生和毒性的早期事件，特别是在内质网内，对于充分理解在细胞功能障碍仍然可逆的阶段设计阻断疾病的治疗方法至关重要。早老素的生物学、细胞表面和细胞内靶点Abeta聚集在小胶质-神经元相互作用和脉管系统上，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。将描述新的动物模型和临床研究的见解，以及与阿尔茨海默病和脑血管淀粉样血管病相关的新兴细胞生物学；也就是说，细胞功能障碍是由β诱导的特定分子靶点的参与驱动的，而不是以前认为的大量原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。这种对阿尔茨海默病发病机制的改变提示了未来治疗干预的多个部位。

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.