Inoue Sadayuki
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Amyloid. 2008 Dec;15(4):223-33. doi: 10.1080/13506120802524858.
According to the amyloid pore hypothesis, pores formed by small oligomers of misfolded amyloidogenic proteins cause membrane leakage with the unregulated rapid influx of ions leading to cell death. Ultrastructurally, pores reconstituted in vitro have mainly been characterised so far, and the presence of in situ pores in the amyloid tissues has not yet been demonstrated. In this study, the presence of in situbeta amyloid (Abeta) pores was shown with high resolution transmission electron microscopy, in the neuronal cell membrane as well as in the membrane of mitochondria-like organelles in the brain with Alzheimer's disease. They are 16 nm wide and 11 nm long flat columnar structures made up of a single cylindrical layer (wall) of laterally associated Abeta protofilaments which surrounds a 10 nm wide opening or lumen. Protofilaments are the basic unit of the fibrils of all amyloid-forming proteins and peptides. Individual extracellular Abeta protofilaments were 2-3 nm wide straight tubular structures with helical wall formed by the tight coiling of 1 nm wide Abeta filaments. These in situ Abeta pores are similar but not identical to in vitro reconstituted Abeta pores.
根据淀粉样蛋白孔假说，由错误折叠的淀粉样蛋白生成蛋白的小寡聚体形成的孔会导致膜泄漏，离子不受控制地快速涌入，从而导致细胞死亡。在超微结构方面，到目前为止，体外重构的孔主要得到了表征，而淀粉样蛋白组织中原位孔的存在尚未得到证实。在本研究中，通过高分辨率透射电子显微镜显示了原位β淀粉样蛋白（Aβ）孔的存在，存在于患有阿尔茨海默病的大脑的神经元细胞膜以及线粒体样细胞器的膜中。它们是宽16nm、长11nm的扁平柱状结构，由横向关联的Aβ原纤维的单个圆柱形层（壁）组成，围绕着一个宽10nm的开口或管腔。原纤维是所有形成淀粉样蛋白的蛋白质和肽的纤维的基本单位。单个细胞外Aβ原纤维是宽2 - 3nm的直管状结构，具有由1nm宽的Aβ细丝紧密盘绕形成的螺旋壁。这些原位Aβ孔与体外重构的Aβ孔相似但并不相同。
