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.
Bobich
Joseph A
JA
Department of Chemistry, Texas Christian University, Fort Worth, TX 76129, USA. j.bobich@tcu.edu
Zheng
Qian
Q
Campbell
Arezoo
A
D000544:Alzheimer Disease / Q000139:chemically induced* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000032:analysis / Q000494:pharmacology* / Q000633:toxicity*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008297:Male; D009410:Nerve Degeneration / Q000473:pathology*; D009411:Nerve Endings / Q000187:drug effects* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D058225:Plaque, Amyloid / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid; D009638:Norepinephrine