Rosuvastatin and thapsigargin modulate γ-secretase gene expression and APP processing in a human neuroglioma model

Alessio Crestini, Paola Piscopo, Mariavittoria Iazeolla, Diego Albani, Roberto Rivabene, Gianluigi Forloni, Annamaria Confaloni

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to slow neuronal loss in several brain regions. It is characterised by the presence of cerebral senile plaques comprised of aggregated amyloid-β peptides. Transcriptional regulation of the γ-secretase complex, which cleaves the β-amyloid precursor protein to produce Aβ-peptides, could modulate the pathological phenotype of AD patients. This study investigates whether rosuvastatin, an HMG-CoA reductase inhibitor, modulates the expression of genes involved in the function of the γ-secretase complex, in a human cellular model for Aβ peptide accumulation. In particular, we analysed the effect of the statin combined with apoptotic induction. Experimental apoptosis was induced by thapsigargin treatment, a drug that depletes intracellular calcium stores via inhibition of the calcium ATPase pump. Notably, systemic calcium dysregulation accompanies almost all of the brain pathology processes observed in AD. We found differential transcriptional regulation of some γ-secretase cofactors relative to rosuvastatin treatment, in cells expressing Swedish mutant APP. Interestingly, this statin downregulated the transcription of some enzyme cofactors, similar to treatment with thapsigargin. However, rosuvastatin neither affected the basal Aβ levels nor counteracted APP processing or Aβ over-production triggered by the thapsigargin. Our results provide evidence that rosuvastatin alters gene expression of the γ-secretase complex without affecting enzyme activity.

Original languageEnglish
Pages (from-to)461-469
Number of pages9
JournalJournal of Molecular Neuroscience
Volume43
Issue number3
DOIs
Publication statusPublished - Mar 2011

Keywords

  • Aβ peptides
  • Gene expression
  • H4 neuroglioma cells
  • Statin
  • Thapsigargin

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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