School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
Biochem J. 2012 Jan 15;441(2):579-90. doi: 10.1042/BJ20110749.
Aβ42 [amyloid-β peptide-(1-42)] plays a central role in Alzheimer's disease and is known to have a detrimental effect on neuronal cell function and survival when assembled into an oligomeric form. In the present study we show that administration of freshly prepared Aβ42 oligomers to a neuroblastoma (SH-SY5Y) cell line results in a reduction in survival, and that Aβ42 enters the cells prior to cell death. Immunoconfocal and immunogold electron microscopy reveal the path of the Aβ42 with time through the endosomal system and shows that it accumulates in lysosomes. A 24 h incubation with Aβ results in cells that have damaged lysosomes showing signs of enzyme leakage, accumulate autophagic vacuoles and exhibit severely disrupted nuclei. Endogenous Aβ is evident in the cells and the results of the present study suggest that the addition of Aβ oligomers disrupts a crucial balance in Aβ conformation and concentration inside neuronal cells, resulting in catastrophic effects on cellular function and, ultimately, in cell death.
Aβ42（淀粉样β肽-(1-42)）在阿尔茨海默病中起核心作用，当组装成寡聚体形式时，已知对神经元细胞功能和存活有不利影响。在本研究中，我们表明，将新制备的 Aβ42 寡聚体施用于神经母细胞瘤（SH-SY5Y）细胞系会导致存活减少，并且 Aβ42 在细胞死亡之前进入细胞。免疫荧光和免疫金电子显微镜显示了 Aβ42 在时间上通过内体系统的路径，并表明它在溶酶体中积累。用 Aβ孵育 24 小时会导致溶酶体受损的细胞显示出酶泄漏的迹象，积累自噬空泡，并表现出严重破坏的核。细胞内存在内源性 Aβ，本研究结果表明，添加 Aβ 寡聚体破坏了神经元细胞内 Aβ 构象和浓度的关键平衡，对细胞功能产生灾难性影响，最终导致细胞死亡。
