EAPSI: Understanding the Role of the Protein Cystatin C in Alzheimer's Disease

阿尔茨海默病是一种影响全世界许多人的神经系统疾病。虽然目前治疗这种疾病的方法很少，但已经确定了一些可能的药物靶点风险因素。重要的证据指向淀粉样蛋白-一种在大脑周围液体中发现的蛋白质片段-是致病因子。这种蛋白质的异常行为已被证明会导致神经元死亡，尽管其毒性途径尚不清楚。最近，在脑液中发现的其他蛋白质已被证明与淀粉样蛋白相互作用。值得注意的是，胱抑素c已被证明与β淀粉样蛋白结合并减少神经元死亡。该项目将重点了解胱抑素c结合淀粉样蛋白- β的方式；这可以帮助未来的研究人员设计出更有效的治疗阿尔茨海默病的药物。这项研究将与日本理化学研究所（Riken research Institute）的著名蛋白质相互作用专家Tamotsu Zako博士合作进行。传统的Alpha-beta模型；相关的神经毒性遵循所谓的“淀粉样蛋白级联假说”。在这个模型中，低分子量的α - β形成淀粉样蛋白种子，作为蛋白质细丝和原纤维快速生长的模板。新的证据表明，α - β的可溶性低聚物种；可能是这种蛋白质聚集体中毒性最大的一种。有趣的是，研究表明胱抑素c可以结合和隔离α - β；在淀粉样蛋白发育的早期阶段，防止出现更大的淀粉样蛋白种类。这种结合的机制尚不清楚。该项目将利用一种新型染料分子来探测结合蛋白复合物的结构细节，并将该结构与胱抑素c可能的神经保护作用联系起来。NSF EAPSI奖是与日本科学促进会合作资助的。

Alzheimer's disease is a neurological disorder which affects a large number of people worldwide. Though little can be done at present to treat the disease, a number of risk factors have been identified as possible drug targets. Significant evidence points to amyloid-beta, a protein fragment found in the fluid surrounding the brain, as the disease-causing agent. Abnormal behavior of this protein has been shown to result in neuron death, though the toxic pathway is poorly understood. Recently, other proteins found in the brain fluid have been shown to interact with amyloid-beta. Notably, cystatin c has been shown to bind amyloid-beta and reduce neuron death. This project will focus on understanding the manner in which cystatin c binds amyloid-beta;, which could help future researchers design more effective drugs against Alzheimer's disease. This research will be conducted in collaboration with Dr. Tamotsu Zako, a noted expert on protein interactions at Riken Research Institute in Japan. The traditional model of Alpha-beta;-related neurotoxicity follows the so-called "amyloid cascade hypothesis." In this model, low molecular weight species of alpha-beta form amyloid seeds which act as a template for rapid growth of protein filaments and fibrils. New evidence has revealed that soluble oligomeric species of alpha-beta; may be the most toxic form of this protein aggregate. Interestingly, it has been shown that cystatin c can bind and sequester alpha-beta; during the early stages of amyloid development, preventing the appearance of larger amyloid species. The mechanism of this binding is poorly understood. This project will utilize a novel dye molecule to probe for structural details of the bound protein complexes and relate that structure to possible cystatin c neuroprotective effects. This NSF EAPSI award is funded in collaboration with the Japan Society for the Promotion of Science.