Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid-induced Ca2+ hyperexcitation

[摘要] Beta-amyloid (A beta) peptide accumulation has long been implicated in the pathogenesis of Alzheimer's disease (AD). Hippocampal network hyperexcitability in the early stages of the disease leads to increased epileptiform activity and eventually cognitive decline. We found that acute application of 250 nM soluble A beta 42 oligomers increased Ca2+ activity in hippocampal neurons in parallel with a significant decrease in activity in A beta 42-treated interneurons. A potential target of A beta 42 is the nicotinic acetylcholine receptor (nAChR). Three major subtypes of nAChRs (alpha 7, alpha 4 beta 2, and alpha 3 beta 4) have been reported in the human hippocampus. Simultaneous inhibition of both alpha 7 and alpha 4 beta 2 nAChRs mimicked the A beta 42 effects on both excitatory and inhibitory neurons. However, inhibition of all 3 subtypes showed the opposite effect. Importantly, simultaneous activation of alpha 7 and alpha 4 beta 2 nAChRs was required to reverse A beta 42-induced neuronal hyperexcitation. We suggest co-activation of alpha 7 and alpha 4 beta 2 nAChRs is required to reverse A beta 42-induced Ca2+ hyperexcitation. (C) 2019 Elsevier Inc. All rights reserved.

[发布日期] 2019-12-01

[关键词] Alzheimer's disease;Hyperexcitation;Nicotinic acetylcholine receptor;Beta-amyloid;Co-activation;Disinhibition