| First Author | Liu Q | Year | 2013 |
| Journal | J Neurosci | Volume | 33 |
| Issue | 17 | Pages | 7253-63 |
| PubMed ID | 23616534 | Mgi Jnum | J:328384 |
| Mgi Id | MGI:6839675 | Doi | 10.1523/JNEUROSCI.3235-12.2013 |
| Citation | Liu Q, et al. (2013) A novel nicotinic mechanism underlies beta-amyloid-induced neuronal hyperexcitation. J Neurosci 33(17):7253-63 |
| abstractText | 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-beta1-42 (Abeta). However, the underlying mechanisms of how Abeta causes neuronal hyperexcitation remain unclear. Here, we report that exposure to pathologically relevant levels of Abeta induces Abeta form-dependent, concentration-dependent, and time-dependent neuronal hyperexcitation in primary cultures of mouse hippocampal neurons. Similarly, Abeta exposure increases levels of nicotinic acetylcholine receptor (nAChR) alpha7 subunit protein on the cell surface and alpha7-nAChR function, but not alpha7 subunit mRNA, suggesting post-translational upregulation of functional alpha7-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 alpha7 subunits and assembled alpha7-nAChRs to the cell surface. Abeta exposure-induced alpha7-nAChR functional upregulation occurs before there is expression of neuronal hyperexcitation. Pharmacological inhibition using an alpha7-nAChR antagonist or genetic deletion of nAChR alpha7 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 alpha7-nAChRs are necessary for production of Abeta-induced neuronal hyperexcitation and possibly AD pathogenesis. This novel mechanism involving alpha7-nAChRs in mediation of Abeta effects provides potentially new therapeutic targets for treatment of AD. |
