Protection against the Neurotoxic Effects of beta-Amyloid Peptide on Cultured Neuronal Cells by Lovastatin Involves Elevated Expression of alpha 7 Nicotinic Acetylcholine Receptors and Activating Phosphorylation of Protein Kinases

摘要

The treatment of neurodegenerative diseases with statins has drawn increasing attention, but the related molecular mechanisms remain elusive. To examine the pleiotropic cholesterol-independent effects of statins in connection with the treatment of Alzheimer disease, we probed the influence of Lovastatin on the metabolism of amyloid precursor protein (APP), expression of nicotinic acetylcholine receptors (nAChRs), and activity of mitogen-activated protein kinase (MAPK) in primary cultured neurons and SH-SY5Y cells overexpressing human APP670/671. Lovastatin attenuated the neurotoxic effects of beta-amyloid peptide (A beta) and affected the metabolism of APP, reducing levels of A beta 1 to A beta 42 and beta-site amyloid precursor protein-cleaving enzyme 1; enhancing those of alpha APP, disintegrin metalloproteinase domain-containing protein 10, and beta-site amyloid precursor protein-cleaving enzyme 2; and up-regulating expression of alpha 7 nAChR and stimulating phosphorylation of extracellular signal regulated kinase (ERK)1/2. Interestingly, methyllycaconitine, an antagonist of alpha 7 nAChR, attenuated this effect on aAPP, but not on phospho-ERK1/2; whereas U0126, an inhibitor of MAPK/ERK kinase/ERK, blocked both the elevated expression of alpha 7 nAChR and enhanced secretion of alpha APP. Our findings indicate that Lovastatin up-regulates expression of alpha 7 nAChR by a mechanism involving activation of the MAPK/ERK pathway, which may result in diminished production of A beta.