Regulation of intracellular calcium in cortical neurons transgenic for human Abeta40 and Abeta42 following nutritive challenge.

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+)](i) 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+)](i) following TFW, while elevation in [Ca(2+)](i) 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+)](i). 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.