The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein.
The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has neurotrophic as well as anti-apoptotic properties and is involved in learning and memory processes. Its specific G protein-coupled receptor PAC1 is expressed in several central nervous system (CNS) regions, including the hippocampal formation. Here we examined the effect of PAC1 receptor activation on alpha-secretase cleavage of the amyloid precursor protein (APP) and the production of secreted APP (APPsalpha). Stimulation of endogenously expressed PAC1 receptors with PACAP in human neuroblastoma cells increased APPsalpha secretion, which was completely inhibited by the PAC1 receptor specific antagonist PACAP-(6-38). In HEK cells stably overexpressing functional PAC1 receptors, PACAP-27 and PACAP-38 strongly stimulated alpha-secretase cleavage of APP. The PACAP-induced APPsalpha production was dose dependent and saturable. This increase of alpha-secretase activity was completely abolished by hydroxamate-based metalloproteinase inhibitors, including a preferential ADAM 10 inhibitor. By using several specific protein kinase inhibitors, we show that the MAP-kinase pathway [including extracellular-regulated kinase (ERK) 1 and ERK2] and phosphatidylinositol 3-kinase mediate the PACAP-induced alpha-secretase activation. Our findings provide evidence for a role of the neuropeptide PACAP in stimulation of the nonamyloidogenic pathway, which might be related to its neuroprotective properties.
Kojro
Elzbieta
E
Institute of Biochemistry, Johannes Gutenberg University, Becherweg, Mainz, Germany. kojro@uni-mainz.de
Postina
Rolf
R
Buro
Corinna
C
Meiringer
Christoph
C
Gehrig-Burger
Katja
K
Fahrenholz
Falk
F
D051722:ADAM Proteins / Q000032:analysis; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D000262:Adenylyl Cyclases / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002118:Calcium / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007668:Kidney; D008565:Membrane Proteins / Q000032:analysis; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000473:pathology; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D011493:Protein Kinase C / Q000502:physiology; D011499:Protein Processing, Post-Translational; D051381:Rats; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000819:agonists / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D000077191:Wortmannin
D051722:ADAM Proteins; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D000262:Adenylyl Cyclases; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor; D000730:Androstadienes; D016282:Aspartic Acid Endopeptidases; D002118:Calcium; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D010450:Endopeptidases; D048049:Extracellular Signal-Regulated MAP Kinases; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011493:Protein Kinase C; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011993:Recombinant Fusion Proteins; D000077191:Wortmannin; C115163:CREB1 protein, human; C509280:BACE1 protein, human; C098339:ADAM9 protein, human; C491236:ADAM10 protein, human