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 journalArticlepeer-review

20 Scopus citations

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
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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