Regulation of intracellular calcium in cortical neurons transgenic for human Aβ40 and Aβ42 following nutritive challenge

International Journal of Clinical and Experimental Medicine

Najeeb A Shirwany¹  Jun Xie¹  Qing Guo¹ 

关键词: Amyloid β-peptide;    intracellular calcium;    InsP3R;    endoplasmic reticulum;    transgenic mice;   

DOI  :  

学科分类：医学（综合）

来源: e-Century Publishing Corporation

【 摘 要 】

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 β40 (Aβ40) and Amyloid β42 (Aβ42), are considered to be critical in the neurodegeneration seen in AD. However, in transgenic mice that overexpress human Aβ40 or Aβ42, it was shown that Aβ42 was much more amyloidogenic than Aβ40. In contrast to this observation, we have found that cultured cortical neurons from mice transgenic for human Aβ40 and for Aβ42 are both and statistically equally vulnerable to nutritive challenge induced by trophic factor withdrawal (TFW). Aberrant regulation of InsP₃R (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 Aβ. We now report that Aβ40 and Aβ42 equally exacerbated intracellular calcium response to TFW in cortical neurons following TFW. When bradykinin (BK), a potent stimulant of InsP₃R-mediated calcium release from ER, was applied to these cells, wild-type (WT) neurons exhibited a steep rise in [Ca²⁺]_i but this was not observed in either Aβ transgenic type. Similarly, when 1 μM Xestopongin C (XeC), a specific blocker of InsP₃R, was applied to these neurons, WT cells showed a significant attenuation of increase in [Ca²⁺]_i following TFW, while elevation in [Ca²⁺]_i induced by TFW remained largely unchanged in Aβ40 and Aβ42 cells. Finally, when we treated these cells with a Ca²⁺ chelator (BAPTA; 10 μM), all three cell types had a marked attenuation of [Ca²⁺]_i. These findings indicate that the exacerbated calcium dysregulation following TFW in Aβ 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 Aβ42, might not necessarily be significantly more neurotoxic than a less or non-amyloidogenic Abeta species, such as Aβ40.

【 授权许可】

Unknown