A Novel Nicotinic Mechanism Underlies β-Amyloid-Induced Neuronal Hyperexcitation

There is a significantly elevated incidence of epilepsy in Alzheimer's disease (AD). Moreover, there is neural hyperexcitation/synchronization in transgenic mice expressing abnormal levels or forms of amyloid precursor protein and its presumed, etiopathogenic product, amyloid-beta(1) (42) (A beta). However, the underlying mechanisms of how A beta causes neuronal hyperexcitation remain unclear. Here, we report that exposure to pathologically relevant levels of A beta induces A beta form-dependent, concentration-dependent, and time-dependent neuronal hyperexcitation in primary cultures of mouse hippocampal neurons. Similarly, A beta exposure increases levels of nicotinic acetylcholine receptor (nAChR) alpha 7 subunit protein on the cell surface and alpha 7-nAChR function, but not alpha 7 subunit mRNA, suggesting post-translational upregulation of functional alpha 7-nAChRs. These effects are prevented upon coexposure to brefeldin A, an inhibitor of endoplasmic reticulum-to-Golgi protein transport, consistent with an effect on trafficking of alpha 7 subunits and assembled alpha 7-nAChRs to the cell surface. A beta exposure-induced alpha 7-nAChR functional upregulation occurs before there is expression of neuronal hyperexcitation. Pharmacological inhibition using an alpha 7-nAChR antagonist or genetic deletion of nAChR alpha 7 subunits prevents induction and expression of neuronal hyperexcitation. Collectively, these results, confirmed in studies using slice cultures, indicate that functional activity and perhaps functional upregulation of alpha 7-nAChRs are necessary for production of A beta-induced neuronal hyperexcitation and possibly AD pathogenesis. This novel mechanism involving alpha 7-nAChRs in mediation of A beta effects provides potentially new therapeutic targets for treatment of AD.