Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs

PLoS One. 2008 Jul 23;3(7):e2718. doi: 10.1371/journal.pone.0002718.

Abstract

Dysregulation of intracellular Ca(2+) homeostasis may underlie amyloid beta peptide (Abeta) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Abeta(1-42) oligomers, the assembly state correlating best with cognitive decline in AD, but not Abeta fibrils, induce a massive entry of Ca(2+) in neurons and promote mitochondrial Ca(2+) overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Abeta oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca(2+) overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca(2+) overload, cytochrome c release and cell death induced by Abeta oligomers. Our results indicate that i) mitochondrial Ca(2+) overload underlies the neurotoxicity induced by Abeta oligomers and ii) inhibition of mitochondrial Ca(2+) overload provides a novel mechanism of neuroprotection by NSAIDs against Abeta oligomers and AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / chemistry*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Apoptosis
  • Calcium / chemistry*
  • Calcium / metabolism
  • Cerebellum / metabolism
  • Cytochromes c / metabolism
  • Membrane Potentials
  • Mitochondria / metabolism*
  • Models, Biological
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species

Substances

  • Amyloid beta-Peptides
  • Anti-Inflammatory Agents, Non-Steroidal
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Cytochromes c
  • Calcium