Shirwany Najeeb A, Xie Jun, Guo Qing
Department of Physiology, University of Oklahoma Health Sciences Center Oklahoma City, OK 73014, USA.
Int J Clin Exp Med. 2009 Jun 12;2(2):149-58.
The pathogenesis of Alzheimer's Disease (AD) is not fully understood. Amyloid plaques could be causally linked to neuronal loss in AD. Two proteolytic products of the Amyloid Precursor Protein (APP), Amyloid beta40 (Abeta40) and Amyloid beta42 (Abeta42), are considered to be critical in the neurodegeneration seen in AD. However, in transgenic mice that overexpress human Abeta40 or Abeta42, it was shown that Abeta42 was much more amyloidogenic than Abeta40. In contrast to this observation, we have found that cultured cortical neurons from mice transgenic for human Abeta40 and for Abeta42 are both and statistically equally vulnerable to nutritive challenge induced by trophic factor withdrawal (TFW). Aberrant regulation of InsP(3)R (Inositol triphosphate receptor)-mediated calcium release has been implicated in neuronal cell death. It is however not clear whether this pathway plays a critical role in cortical neurons transgenic for different species of human Abeta. We now report that Abeta40 and Abeta42 equally exacerbated intracellular calcium response to TFW in cortical neurons following TFW. When bradykinin (BK), a potent stimulant of InsP(3)R-mediated calcium release from ER, was applied to these cells, wild-type (WT) neurons exhibited a steep rise in Ca(2+) but this was not observed in either Abeta transgenic type. Similarly, when 1 muM Xestopongin C (XeC), a specific blocker of InsP(3)R, was applied to these neurons, WT cells showed a significant attenuation of increase in Ca(2+) following TFW, while elevation in Ca(2+) induced by TFW remained largely unchanged in Abeta40 and Abeta42 cells. Finally, when we treated these cells with a Ca(2+) chelator (BAPTA; 10 muM), all three cell types had a marked attenuation of Ca(2+). These findings indicate that the exacerbated calcium dysregulation following TFW in Abeta transgenic neurons are likely to be mediated by calcium channels other than ER InsP3R receptors. Overall, our results also suggest that a highly amyloidogenic Abeta species, such as Abeta42, might not necessarily be significantly more neurotoxic than a less or non-amyloidogenic Abeta species, such as Abeta40.
阿尔茨海默病（AD）的发病机制尚未完全明确。淀粉样斑块可能与AD中的神经元丢失存在因果关系。淀粉样前体蛋白（APP）的两种蛋白水解产物，淀粉样β40（Aβ40）和淀粉样β42（Aβ42），被认为在AD所见的神经退行性变中起关键作用。然而，在过表达人Aβ40或Aβ42的转基因小鼠中，结果显示Aβ42比Aβ40更具淀粉样变性。与这一观察结果相反，我们发现来自人Aβ40和Aβ42转基因小鼠的培养皮质神经元在营养因子撤除（TFW）诱导的营养挑战下均同样且在统计学上同等易损。肌醇三磷酸受体（InsP(3)R）介导的钙释放的异常调节与神经元细胞死亡有关。然而，尚不清楚该途径在不同种类人Aβ转基因的皮质神经元中是否起关键作用。我们现在报告，在TFW后，Aβ40和Aβ42在皮质神经元中同等程度地加剧了对TFW的细胞内钙反应。当将缓激肽（BK），一种InsP(3)R介导的从内质网释放钙的强效刺激剂，应用于这些细胞时，野生型（WT）神经元的Ca(2+)急剧上升，但在任何一种Aβ转基因类型中均未观察到这种情况。同样，当将1 μM西司普龙C（XeC），一种InsP(3)R的特异性阻滞剂，应用于这些神经元时，WT细胞在TFW后Ca(2+)的增加显著减弱，而TFW诱导的Aβ40和Aβ42细胞中Ca(2+)的升高基本保持不变。最后，当我们用钙螯合剂（BAPTA；10 μM）处理这些细胞时，所有三种细胞类型的Ca(2+)均显著减弱。这些发现表明，Aβ转基因神经元在TFW后加剧的钙调节异常可能由内质网InsP3R受体以外的钙通道介导。总体而言，我们的结果还表明，一种高度淀粉样变性的Aβ种类，如Aβ42，不一定比一种较少或非淀粉样变性的Aβ种类，如Aβ40，具有明显更强的神经毒性。
