Structure determination by vibrational spectroscopy

 描述(由申请人提供)：尽管几十年来不断深入的研究，但迟发性阿尔茨海默病(LOAD)的“原因”仍然很大程度上未知。目前有500多万人患有这种疾病，它是美国第六大死亡原因，而且没有可用的治疗方法来改变其无情的进程。这种疾病的特点是 A？多肽在大脑中以纤维形式积累，并以纤维形式聚集在一起 组织学上可观察到的斑块是由死亡神经元发出的声音。我们假设A？多肽在形态上难以区分的纤维中至少有几个不同的构象，并且这些构象在热力学稳定性上是不同的。当纤维成熟时，它们很可能会接近越来越稳定的结构，所以在成熟过程中演变的光谱信号应该揭示决定稳定性的相互作用的性质。因此，我们的具体目标是将纤维形成的条件与形成的TE纤维的稳定性联系起来，并确定导致足够稳定的纤维存在于脑组织中的因素。这是宾夕法尼亚大学超快光学过程实验室的一个“驱动力生物医学项目”，该实验室是美国国立卫生研究院赞助的研究资源。相关性：我们的方法有可能揭示控制阿尔茨海默病淀粉样蛋白形成的特定化学机制，这将是我们在理解其发病机制方面向前迈出的一大步。

 DESCRIPTION (provided by applicant): The "cause" of "late-onset" Alzheimer's disease (LOAD) remains largely unknown despite decades of increasingly intense study. More than 5 million people currently have this disease, it is the 6th leading cause of death in the US, and there are no treatments available that alter its relentless course. The disease is characterized by the accumulation of Aß peptides in the brain as fibrils, and the collection of fibrils together as histologically observable plaques sounded by dead neurons. We hypothesize that Aß peptides assume at least several distinct conformations in morphologically indistinguishable fibrils, and that these conformations vary in their thermodynamic stability. It is likely that fibrils approach increasingly stable structures as they mature, so the spectroscopic signals that evolve in the course of maturation should reveal the nature of the interactions that determine stability. Accordingly, our specific aims are to link the conditions of fibril formation to the stability of te fibrils that form and determine the factors that lead to fibrils that are sufficiently stable to pesist in brain tissue. This is a "driving biomedical project" in the Ultrafast Optical Processes Laboratory at the University of Pennsylvania, an NIH-sponsored Research Resource. Relevance: Our approach has the potential to uncover specific chemical mechanisms that govern amyloid formation in Alzheimer's disease, which would represent a giant step forward in our understanding of its pathogenesis.