Incubation of nerve endings with a physiological concentration of Abeta1-42 activates CaV2.2(N-Type)-voltage operated calcium channels and acutely increases glutamate and noradrenaline release.

We wish to understand the normal function of amyloid-beta peptides (Abeta) and to see if they destabilize neuronal calcium homeostasis [Mattson et al., J. Neurosci. 12 (1992), 376-389]. We observed that a physiological concentration (10 nM) of Abeta1-42 increased both glutamate and noradrenaline exocytosis from rat cortical nerve endings at least in part by activation of N-type Ca2+ channels. Abeta oligomers rather than monomers or fibrils probably are the most active form. Three alternatively-proposed effects of Abeta (reactive oxygen species formation, membrane perforation, and disruption of Ca2+ stores) also were tested by incubating nerve endings with a relatively high (by this study's standards) concentration of Abeta1-42(100 nM). None of the three proposed effects were detected during these incubations. These results support the hypothesis that persistent elevations of Abeta, which normally operates as a modulator of N-type voltage gated calcium channels, could increase internal nerve ending Ca2+ and excitatory neurotransmitter release to produce the early neurotoxic effects that eventually lead to Alzheimer's disease.