Beta-secretase BACE1 is differentially controlled through muscarinic acetylcholine receptor

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

    Research output: Contribution to journalArticle

    41 Citations (Scopus)

    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

    Fingerprint

    Amyloid Precursor Protein Secretases
    Muscarinic Receptors
    Amyloid beta-Protein Precursor
    Cholinergic Agonists
    Amyloid
    Alzheimer Disease
    MAP Kinase Kinase Kinases
    Phorbol Esters
    Colforsin
    Enzymes
    Cyclic AMP-Dependent Protein Kinases
    Neuroblastoma
    Adenylyl Cyclases
    Protein Kinase C
    Cholinergic Agents
    Up-Regulation
    Cell Line
    Peptides
    Therapeutics

    Keywords

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

    ASJC Scopus subject areas

    • Neuroscience(all)

    Cite this

    Beta-secretase BACE1 is differentially controlled through muscarinic acetylcholine receptor. / Züchner, Thole; Perez-Polo, J. Regino; Schliebs, Reinhard.

    In: Journal of Neuroscience Research, Vol. 77, No. 2, 15.07.2004, p. 250-257.

    Research output: Contribution to journalArticle

    Züchner, Thole ; Perez-Polo, J. Regino ; Schliebs, Reinhard. / Beta-secretase BACE1 is differentially controlled through muscarinic acetylcholine receptor. In: Journal of Neuroscience Research. 2004 ; Vol. 77, No. 2. pp. 250-257.
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