Bateman David A, McLaurin JoAnne, Chakrabartty Avijit
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
BMC Neurosci. 2007 May 2;8:29. doi: 10.1186/1471-2202-8-29.
Aggregation of the amyloid peptides, Abeta40 and Abeta42, is known to be involved in the pathology of Alzheimer's disease (AD). Here we investigate the relationship between peptide aggregation and cell surface binding of three forms of Abeta (Abeta40, Abeta42, and an Abeta mutant).
Using confocal microscopy and flow cytometry with fluorescently labelled Abeta, we demonstrate a correlation between the aggregation propensity of the Alzheimer amyloid peptides and their neuronal cell surface association. We find that the highly aggregation prone Abeta42 associates with the surface of neuronal cells within one hour, while the less aggregation prone Abeta40 associates over 24 hours. We show that a double mutation in Abeta42 that reduces its aggregation propensity also reduces its association with the cell surface. Furthermore, we find that a cell line that is resistant to Abeta cytotoxicity, the non-neuronal human lymphoma cell line U937, does not bind either Abeta40 or Abeta42.
Taken together, our findings reveal that amyloid peptide aggregation propensity is an essential determinant of neuronal cell surface association. We anticipate that our approach, involving Abeta imaging in live cells, will be highly useful for evaluating the efficacy of therapeutic drugs that prevent toxic Abeta association with neuronal cells.
已知淀粉样肽β-淀粉样蛋白40（Aβ40）和β-淀粉样蛋白42（Aβ42）的聚集与阿尔茨海默病（AD）的病理过程有关。在此，我们研究了三种形式的Aβ（Aβ40、Aβ42和一种Aβ突变体）的肽聚集与细胞表面结合之间的关系。
使用共聚焦显微镜和带有荧光标记Aβ的流式细胞术，我们证明了阿尔茨海默淀粉样肽的聚集倾向与其神经元细胞表面结合之间存在相关性。我们发现，极易聚集的Aβ42在一小时内与神经元细胞表面结合，而较不易聚集的Aβ40则在24小时以上才结合。我们表明，Aβ42中的双重突变降低了其聚集倾向，同时也降低了其与细胞表面的结合。此外，我们发现对Aβ细胞毒性具有抗性的细胞系，即非神经元人类淋巴瘤细胞系U937，不结合Aβ40或Aβ42。
综上所述，我们的研究结果表明淀粉样肽聚集倾向是神经元细胞表面结合的一个重要决定因素。我们预计，我们涉及活细胞中Aβ成像的方法，将对评估预防有毒Aβ与神经元细胞结合的治疗药物的疗效非常有用。
