Beta-secretase BACE1 is differentially controlled through muscarinic acetylcholine receptor signaling.
The beta-amyloid peptides derived by proteolytic cleavage from the amyloid precursor protein (APP) play a major role in the pathogenesis of Alzheimer's disease (AD) by forming aggregated, fibrillary complexes that have been shown to be neurotoxic. The beta-site APP-cleaving enzyme (BACE1) has been identified as the key enzyme leading to beta-amyloid formation, and cholinergic mechanisms have been shown to control APP processing. The present study sought to determine whether BACE1 expression is controlled by muscarinic acetylcholine receptor (mAChR) subtypes in the neuroblastoma cell line SK-SH-SY5Y. Stimulation of cells with the M1/M3-selective mAChR agonist talsaclidine for 1 hr resulted in a dose-dependent increase in BACE1 expression up to twofold over basal levels. Similar effects of BACE1 up-regulation were observed when protein kinase C was directly activated by phorbol esters. However, when the MAP kinases MEK/ERK were inhibited, BACE1 expression was no longer up-regulated by the activation of M1-mAChR. In contrast, BACE1 expression was suppressed by stimulation of M2-mediated pathways via selective M2-agonist binding or direct activation of adenylate cyclase with forskolin, an effect that was prevented by inhibiting protein kinase A. These results may explain the observed deterioration of AD patients after initial improvements with AChE inhibitor or M1-mAChR agonist treatment.
Züchner
Thole
T
Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, Leipzig, Germany.
Perez-Polo
J Regino
JR
Schliebs
Reinhard
R
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D043643:Receptor, Muscarinic M1 / Q000819:agonists / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000819:agonists / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017211:Treatment Failure; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D018721:Muscarinic Agonists; D010703:Phorbol Esters; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D000262:Adenylyl Cyclases