ABSTRACT
Beta-amyloid (Aß) 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 Aß42 oligomers increased Ca2+ activity in hippocampal neurons in parallel with a significant decrease in activity in Aß42-treated interneurons. A potential target of Aß42 is the nicotinic acetylcholine receptor (nAChR). Three major subtypes of nAChRs (α7, α4ß2, and α3ß4) have been reported in the human hippocampus. Simultaneous inhibition of both α7 and α4ß2 nAChRs mimicked the Aß42 effects on both excitatory and inhibitory neurons. However, inhibition of all 3 subtypes showed the opposite effect. Importantly, simultaneous activation of α7 and α4ß2 nAChRs was required to reverse Aß42-induced neuronal hyperexcitation. We suggest co-activation of α7 and α4ß2 nAChRs is required to reverse Aß42-induced Ca2+ hyperexcitation.
