Beta-amyloid (Aβ) 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 Aβ42 oligomers increased Ca2+ activity in hippocampal neurons in parallel with a significant decrease in activity in Aβ42-treated interneurons. A potential target of Aβ42 is the nicotinic acetylcholine receptor (nAChR). Three major subtypes of nAChRs (α7, α4β2, and α3β4) have been reported in the human hippocampus. Simultaneous inhibition of both α7 and α4β2 nAChRs mimicked the Aβ42 effects on both excitatory and inhibitory neurons. However, inhibition of all 3 subtypes showed the opposite effect. Importantly, simultaneous activation of α7 and α4β2 nAChRs was required to reverse Aβ42-induced neuronal hyperexcitation. We suggest co-activation of α7 and α4β2 nAChRs is required to reverse Aβ42-induced Ca2+ hyperexcitation.
Keywords: Alzheimer's disease; Beta-amyloid; Co-activation; Disinhibition; Hyperexcitation; Nicotinic acetylcholine receptor.
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