Co-Assembly and Ion-Channel Formation of Truncated Amyloid-beta Isoforms in Alzheimer's Disease.

阿尔茨海默病是西方世界第四大常见死因，仅次于癌症、心脏病和中风。它是痴呆症最常见的形式，其特征是小肽-淀粉样β蛋白在大脑中长期积累。疾病的发生与错误折叠的淀粉样β蛋白自我组装成神经毒性聚集体和纤维有关，这些聚集体和纤维以细胞外斑块的形式沉积。几种自然产生的淀粉样β蛋白亚型在突触处释放，长度在38-43个氨基酸之间。最近的研究表明，不同的淀粉样β蛋白亚型的组合可以增强或抑制纤维的形成。我的目的是探索不同的淀粉样β亚型共聚集成单纤维的相对能力，并利用原子力显微镜、透射电子显微镜和冷冻-EM等生物物理技术确定共纤维化的结构机制。这项工作还将得到毒性研究的补充，其中电生理学和原子力显微镜可以用来评估聚集体破坏神经细胞膜完整性和形成神经毒性离子通道的能力。

Alzheimer's disease is the fourth most common cause of death in the Western world, after cancer, heart disease and stroke. It is the most prevalent form of dementia and is characterized by the long-term accumulation of the small peptide, amyloid-beta, within the brain. The onset of disease is linked to the self-assembly of misfolded amyloid-beta into neurotoxic aggregates and fibres which deposit as extracellular plaques. Several naturally-occurring amyloid-beta isoforms are released at the synapse, ranging between 38-43 amino-acids in length. Recent investigations have shown that combinations of different amyloid-beta isoforms can augment or frustrate fibre formation. My aim is to probe the relative ability for different amyloid-beta isoforms to co-aggregate into a single fibres, and to identify the structural mechanism of co-fibrillisation using biophysical techniques such as AFM, TEM and Cryo-EM. This work will also be complemented by toxicity studies, where electrophysiology and AFM can be used to assess the ability of the aggregates to disrupt neuronal cell membrane integrity and form neurotoxic ion channels.