Beta-secretase BACE1 is differentially controlled through muscarinic acetylcholine receptor

Thole Züchner, J. Regino Perez-Polo, Reinhard Schliebs

    Research output: Contribution to journalArticle

    42 Scopus citations

    Abstract

    The β-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 β-site APP-cleaving enzyme (BACE1) has been identified as the key enzyme leading to β-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.

    Original languageEnglish (US)
    Pages (from-to)250-257
    Number of pages8
    JournalJournal of Neuroscience Research
    Volume77
    Issue number2
    DOIs
    StatePublished - Jul 15 2004

    Keywords

    • Beta-secretase
    • Immunoblot
    • Muscarinic receptor
    • SY5Y cells
    • β-amyloid

    ASJC Scopus subject areas

    • Cellular and Molecular Neuroscience

    Fingerprint Dive into the research topics of 'Beta-secretase BACE1 is differentially controlled through muscarinic acetylcholine receptor'. Together they form a unique fingerprint.

  • Cite this