Down-regulation of muscarinic acetylcholine receptor M2 adversely affects the expression of Alzheimer's disease-relevant genes and proteins

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

    Research output: Contribution to journalArticle

    16 Citations (Scopus)

    Abstract

    Beta-amyloid peptides play a major role in the pathogenesis of Alzheimer's disease (AD). Therefore, preventing beta-amyloid formation by inhibition of the beta site amyloid precursor protein-cleaving enzyme (BACE) 1 is considered as a potential strategy to treat AD. Cholinergic mechanisms have been shown to control amyloid precursor protein processing and the number of muscarinic M2-acetylcholine receptors is decreased in brain regions of patients with AD enriched with senile plaques. Therefore, the present study investigates the effect of this M2 muscarinic receptor down-regulation by siRNA on total gene expression and on regulation of BACE1 in particular in SK-SH-SY5Y cells. This model system was used for microarray analysis after carbachol stimulation of siRNA-treated cells compared with carbachol stimulated, non-siRNA-treated cells. The same model system was used to elucidate changes at the protein level by using two-dimensional gels followed by Matrix Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF) analysis. Taken together, the results indicate that the M2 acetylcholine receptor down-regulation in brains of patients with AD has important effects on the expression of several genes and proteins with major functions in the pathology of AD. This includes beta-secretase BACE1 as well as several modulators of the tau protein and other AD-relevant genes and proteins. Moreover, most of these genes and proteins are adversely affected against the background of AD.

    Original languageEnglish (US)
    Pages (from-to)20-32
    Number of pages13
    JournalJournal of Neurochemistry
    Volume95
    Issue number1
    DOIs
    StatePublished - Oct 2005

    Fingerprint

    Muscarinic M2 Receptors
    Muscarinic Receptors
    Alzheimer Disease
    Down-Regulation
    Proteins
    Amyloid beta-Protein Precursor
    Carbachol
    Cholinergic Receptors
    Cholinergic Agents
    Small Interfering RNA
    Brain
    Cells
    tau Proteins
    Amyloid Precursor Protein Secretases
    Amyloid beta-Peptides
    Amyloid Plaques
    Gene Expression Regulation
    Pathology
    Microarray Analysis
    Microarrays

    Keywords

    • Alzheimer's disease
    • Beta site amyloid precursor protein-cleaving enzyme 1
    • Cholinergic system
    • Muscarinic receptor
    • siRNA
    • SK-N-SH-SY5Y cells

    ASJC Scopus subject areas

    • Biochemistry
    • Cellular and Molecular Neuroscience

    Cite this

    Down-regulation of muscarinic acetylcholine receptor M2 adversely affects the expression of Alzheimer's disease-relevant genes and proteins. / Zuchner, Thole; Schliebs, Reinhard; Perez-Polo, J. Regino.

    In: Journal of Neurochemistry, Vol. 95, No. 1, 10.2005, p. 20-32.

    Research output: Contribution to journalArticle

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    abstract = "Beta-amyloid peptides play a major role in the pathogenesis of Alzheimer's disease (AD). Therefore, preventing beta-amyloid formation by inhibition of the beta site amyloid precursor protein-cleaving enzyme (BACE) 1 is considered as a potential strategy to treat AD. Cholinergic mechanisms have been shown to control amyloid precursor protein processing and the number of muscarinic M2-acetylcholine receptors is decreased in brain regions of patients with AD enriched with senile plaques. Therefore, the present study investigates the effect of this M2 muscarinic receptor down-regulation by siRNA on total gene expression and on regulation of BACE1 in particular in SK-SH-SY5Y cells. This model system was used for microarray analysis after carbachol stimulation of siRNA-treated cells compared with carbachol stimulated, non-siRNA-treated cells. The same model system was used to elucidate changes at the protein level by using two-dimensional gels followed by Matrix Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF) analysis. Taken together, the results indicate that the M2 acetylcholine receptor down-regulation in brains of patients with AD has important effects on the expression of several genes and proteins with major functions in the pathology of AD. This includes beta-secretase BACE1 as well as several modulators of the tau protein and other AD-relevant genes and proteins. Moreover, most of these genes and proteins are adversely affected against the background of AD.",
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