| First Author | Cisse M | Year | 2011 |
| Journal | Mol Cell Neurosci | Volume | 47 |
| Issue | 3 | Pages | 223-32 |
| PubMed ID | 21570469 | Mgi Jnum | J:178049 |
| Mgi Id | MGI:5297044 | Doi | 10.1016/j.mcn.2011.04.008 |
| Citation | Cisse M, et al. (2011) ERK1-independent alpha-secretase cut of beta-amyloid precursor protein via M1 muscarinic receptors and PKCalpha/epsilon. Mol Cell Neurosci 47(3):223-32 |
| abstractText | The amyloid precursor protein (betaAPP) undergoes several proteolytic cleavages. While beta- and gamma-secretases are responsible for the production of the 40-43 amino-acid long amyloid beta peptide (Abeta), the alpha-secretase cut performed by the disintegrins ADAM10 and ADAM17, occurs in the middle of the Abeta sequence, thereby preventing its formation and leading to the secretion of the large sAPPalpha neuroprotective fragment. Here we showed that a series of M1 muscarinic receptor agonists dose-dependently stimulated sAPPalpha secretion without interfering with betaAPP subcellular distribution. Carbachol- and PDBu-induced sAPPalpha secretions were blocked by the general PKC inhibitor GF109203X. We established that HEK293 and rhabdhomyosarcoma cells overexpressing constitutively active (CA) PKCalpha or PKCepsilon secrete increased amounts of sAPPalpha while those expressing PKCdelta were unable to modify sAPPalpha recovery. Conversely, the overexpression of PKCalpha or PKCepsilon dominant negative (DN) constructs abolished PDBU-stimulated sAPPalpha secretion, whereas DN-PKCdelta remained inert. In agreement, PKCalpha knockout lowered sAPPalpha recovery in primary cultured fibroblasts. We also demonstrated that the regulated alpha-secretase processing of betaAPP is not controlled by the Extracellular-Regulated Kinase-1/MAP-ERK Kinase (ERK1/MEK) cascade and likely does not require ADAM17 phosphorylation on its threonine735 residue. Because the muscarinic-dependent alpha-secretase-like processing of PrP(c) is fully dependent on ADAM17 phosphorylation on its threonine735 residue by ERK1, these results indicate that a single extracellular signal triggers ADAM17-dependent regulated cleavages of betaAPP and PrP(c) through distinct signalling cascades. This opens new potential therapeutic strategies aimed, in the context of Alzheimer's disease, at selectively activating ADAM17 towards betaAPP without affecting the cleavages of its numerous other substrates. |
