Cell death induced by β-amyloid 1-40 in MES 23.5 hybrid clone: the role of nitric oxide and NMDA-gated channel activation leading to apoptosis

Weidong Le, Luis V. Colom, Wen jie Xie, R. Glenn Smith, Maria Alexianu, Stanley H. Appel

Research output: Contribution to journalArticle

133 Scopus citations

Abstract

The molecular events associated with β-amyloid-induced neuronal injury remain incompletely characterized. Using a substantia nigra/neuroblastoma hybrid cell line (MES 23.5) synthetic β-amyloid 1-40 induced a time and dose-dependent apoptotic cell death which was characterized by cell shrinkage and fragmentation of DNA, and was inhibited by aurintricarboxylic acid (ATA), and cycloheximide (CHX). Following β-amyloid 1-40 treatment, cyclic GMP, an index of NO synthesis, was increased in MES 23.5 cells. The NO scavenger hemoglobin, as well as the NO synthase inhibitors NG-monomethyl-l-arginine acetate (l-NMMA) andl-N5-(1-iminoethyl)ornithine hydrochloride (l-NIO) attenuated such increases. These same inhibitors and scavengers also significantly prevented cytotoxicity. β-Amyloid also induced an early and transient increase in intracellular calcium as monitored with laser scanning confocal microscopy and Fluo-3 imaging. These induced calcium transients could be significantly blocked by theN-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801. Pretreatment with MK-801 or removal of extracellular Ca2+ also reduced β-amyloid-induced NO production and neurotoxicity. Furthermore, β-amyloid neurotoxicity was greatly enhanced in the absence of Mg2+ or in the presence of glutamate or NMDA. These data suggest that β-amyloid can lead to apoptotic cell death through a NO mediated process possibly triggered by Ca2+ entry through activated NMDA-gated channels.

Original languageEnglish (US)
Pages (from-to)49-60
Number of pages12
JournalBrain Research
Volume686
Issue number1
DOIs
StatePublished - Jul 17 1995

Keywords

  • β-Amyloid
  • Alzheimer's disease
  • Calcium
  • N-Methyl-d-aspartic acid
  • Neurotoxicity
  • Nitric oxide

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Molecular Biology
  • Developmental Biology

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