Nicotinic receptor agonists and antagonists increase sAPPα secretion and decrease Aβ levels in vitro

We have earlier reported that A beta were significantly reduced in brains of smoking Alzheimer patients and control subjects compared with non-smokers, as well as in nicotine treated APPsw transgenic mice. To examine the mechanisms by which nicotine modulates APP processing we here measured levels of secreted amyloid precursor protein (sAPP alpha), total sAPP, A beta 40 and A beta 42 in different cell lines expressing different nicotinic receptor (nAChR) subtypes or no nAChRs. Treatment with nicotine increased release of sAPP(x and at the same time lowered A beta levels in both SH-SY5Y and SH-SY5Y/APPsw cells expressing alpha 3 and alpha 7 nAChR subtypes. These effects could also be evoked by co-treatment with the competitive alpha 7 nAChR antagonists alpha-bungarotoxin and methyllycaconitine (MLA), and by these antagonists alone, suggesting that binding to the agonist binding site, rather than activation of the receptor, may be sufficient to trigger changes in APP processing. The nicotine-induced increase in sAPP alpha could only be blocked by co-treatment with the open channel blocker mecamylamine. In addition to nicotine, the agonists epibatidine and cytisine both significantly increased the release of sAPP in M 10 cells expressing the alpha 4/beta 2 nAChR subtype, and this effect was blocked by co-treatment with mecamylamine but not by the alpha 4/beta 2 competitive antagonist dihydro-p-erythroidine. The lack of effect of nicotine on sAPP alpha and A beta levels in HEK 293/APPsw cells, which do not express any nAChRs, demonstrates that the nicotine-induced attenuation of beta-amyloidosis is mediated by nAChRs and not by a direct effect of nicotine. Our data show that nicotinic compounds stimulate the non-amyloidogenic pathway and that alpha 4 and alpha 7 nAChRs play a major role in modulating this process. Nicotinic drugs directed towards specific nAChR subtypes might therefore be beneficial for the treatment of AD not only by lowering A beta production but also by enhance release of neuroprotective sAPP alpha. (C) 2008 Elsevier Ltd. All rights reserved.