EAPSI: Understanding Alzheimer's Disease through Modifying the Electrical Stability between Two Key Amino Acids of an Important Protein

阿尔茨海默病（AD）是一种进行性神经退行性疾病，影响着500万美国老年人，预计到2050年这一数字将增加两倍。阿尔茨海默病目前是美国第六大死因。尽管对阿尔茨海默病进行了数十年的研究，但这种致命疾病仍无法治愈。阿尔茨海默病研究的一个重大挑战是研究使普通蛋白质从天然无毒状态转变为异常有毒形式的机制。通常，蛋白质结构的差异会导致生物活性的急剧改变。不幸的是，这两种截然不同的结构身份之间的快速转变并没有得到很好的理解。实验证据表明，有有利的分子相互作用，稳定异常形式。该奖项支持旨在研究重要AD蛋白淀粉样蛋白- β的两个关键氨基酸之间的电相互作用，以评估蛋白质的结构稳定性的研究。这项研究将在国立台湾大学进行，由Richard Cheng博士指导，他在其中一项实验技术方面的专业知识将对项目的结果至关重要。这项基础阿尔茨海默病研究的实验设计整合了家庭和宿主实验室的专业知识。将采用标准固相肽合成方法合成一系列淀粉样蛋白的肽结构模型，并对产物进行纯化和表征。这些合成肽将包含β淀粉样蛋白片段，这些片段已知会引发不受控制的聚集，随后可以通过放置良好的氢键阻滞剂来抑制。为了探究淀粉样蛋白中两个关键氨基酸（赖氨酸和谷氨酸）之间的静电相互作用，我们将系统地用氨基酸衍生物取代它们。这些修饰应该增强或减少静电相互作用，从而分别导致这些肽的结构稳定或不稳定。郑博士的专业圆二色光谱将用于量化稳定能量。这个项目的结果将提供一个关键的分子相互作用的更深入的见解，可以稳定淀粉样蛋白的有毒形式。这些信息可能会帮助其他AD研究人员进行自己的努力，并导致未来阿尔茨海默病的发现，从而造福社会。该奖项由美国国家科学基金会EAPSI与台湾科学技术部合作资助，支持一名美国研究生的研究。

Alzheimer's disease (AD) is a progressive, neurodegenerative disease that affects 5 million elderly Americans and this number is expected to triple by 2050. AD is currently the 6th leading cause of death in the United States. Despite decades of AD research, there is no cure for this deadly disease. A significant challenge in AD research is studying the mechanism that makes an ordinary protein transform from its natural, non-toxic state to an abnormal, toxic form. Often, differences in protein structure can lead to drastically altered biological activities. Unfortunately, this rapid transition between the two distinct structural identities is not well understood. Experimental evidence suggests that there are favorable molecular interactions that stabilize the abnormal form. This award supports research that aims to study the electrical interaction between two key amino acids of an important AD protein, amyloid-beta, in order to evaluate the protein's structural stability. The research will be conducted at National Taiwan University under the mentorship of Dr. Richard Cheng, whose expertise in one of the experimental techniques will be critical to the outcome of the project.The experimental design of this basic Alzheimer's disease research integrates the specialties from both the home and host laboratories. A series of peptide structural models of amyloid-beta will be synthesized using standard solid-phase peptide synthesis followed by product purification and characterization. These synthetic peptides will incorporate fragments of amyloid-beta that are known to initiate uncontrolled aggregation which can be subsequently suppressed by a well-placed hydrogen-bond blocker. To probe the electrostatic interaction between two key amino acids (lysine and glutamic acid) of amyloid-beta, they will be systematically replaced by amino acid derivatives. The modifications should either enhance or reduce the electrostatic interaction, which can lead to structural stabilization or destabilization of these peptides, respectively. Circular dichorism spectroscopy, a specialty of Dr. Cheng, will be used to quantify the stabilizing energies. The results of this project will afford deeper insights of a key molecular interaction that can stabilize the toxic form of amyloid-beta. This information may assist other AD researchers in their own endeavors and lead to future Alzheimer's disease discoveries that will benefits society. This NSF EAPSI award supports the research of a U.S. graduate student and is funded in collaboration with the Ministry of Science and Technology of Taiwan.