A Novel Nicotinic Mechanism Underlies Î²-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-Î²1- 42 (AÎ²). However, the underlying mechanisms of how AÎ² causes neuronal hyperexcitation remain unclear. Here, we report that exposure to pathologically relevant levels of AÎ² induces AÎ² form-dependent, concentration-dependent, and time-dependent neuronal hyperexcitation in primary cultures of mouse hippocampal neurons. Similarly, AÎ² exposure increases levels of nicotinic acetylcholine receptor (nAChR) Î±7 subunit protein on the cell surface and Î±7-nAChR function, but not Î±7 subunit mRNA, suggesting post-translational upregulation of functional Î±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 ofÎ±7 subunits and assembledÎ±7-nAChRs to the cell surface. AÎ² exposure-inducedÎ±7-nAChR functional upregulation occurs before there is expression of neuronal hyperexcitation. Pharmacological inhibition using anÎ±7-nAChR antagonist or genetic deletion of nAChRÎ±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 Î±7-nAChRs are necessary for production of AÎ²-induced neuronal hyperexcitation and possibly AD pathogenesis. This novel mechanism involving Î±7-nAChRs in mediation of AÎ² effects provides potentially new therapeutic targets for treatment of AD.
Journal of Neuroscience
Digital Object Identifier (DOI)
Liu, Qiang; Xie, Xitao; Lukas, Ronald J.; St.John, Paul A.; and Wu, Jie, "A Novel Nicotinic Mechanism Underlies Î²-Amyloid-Induced Neuronal Hyperexcitation" (2013). Neurobiology. 400.