Acetylcholinesterase inhibitors increase ADAM10 activity by promoting its trafficking in neuroblastoma cell lines

Martina Zimmermann, Fabrizio Gardoni, Elena Marcello, Francesca Colciaghi, Barbara Borroni, Alessandro Padovani, Flaminio Cattabeni, Monica Di Luca

Research output: Contribution to journalArticlepeer-review

Abstract

Acetylcholinesterase inhibitors (AChEIs) are the only currently available drugs for treating Alzheimer's Disease (AD). Some authors have suggested a function of AChEIs not only in the induction of AChE overproduction and alternative splicing shifts but also a possible role of these drugs in amyloid metabolism beyond their well-known symptomatic effect. Here, we investigate the mechanisms of action of the AChEI donepezil on APP (amyloid precursor protein) metabolism and on the activity/trafficking of the alpha-secretase candidate ADAM 10, in differentiated human neuroblastoma cells (SH-SY5Y). In these cells, the activity of AChE is significantly decreased after 2 h of donepezil treatment. Further, SH-SY5Y cells released significantly more sAPPα into the medium, whereas total APP levels in cell lysates were unchanged. Interestingly, treated cells showed increased ADAM 10 levels in membrane compartments. This effect was prevented by pretreatment with tunicamycin or brefeldin, suggesting that donepezil affects trafficking and/or maturation of ADAM 10; additionally, this pretreatment significantly decreased sAPPα levels. Pre-incubation with atropine decreased release of sAPPα significantly but did not revert ADAM 10 activity to control levels further suggesting that donepezil acts not solely through a purely receptor mediated pathway. These findings indicate that donepezil exerts multiple mechanisms involving processing and trafficking of key proteins involved in AD pathogenesis.

Original languageEnglish
Pages (from-to)1489-1499
Number of pages11
JournalJournal of Neurochemistry
Volume90
Issue number6
DOIs
Publication statusPublished - Sep 2004

Keywords

  • Acetylcholinesterase
  • ADAM 10
  • Alzheimer's disease
  • Donepezil
  • Neuroblastoma
  • Trafficking

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Acetylcholinesterase inhibitors increase ADAM10 activity by promoting its trafficking in neuroblastoma cell lines'. Together they form a unique fingerprint.

Cite this