Modulation of mitochondrial calcium as a pharmacological target for Alzheimer's disease

Ageing Res Rev. 2010 Oct;9(4):447-56. doi: 10.1016/j.arr.2010.05.003. Epub 2010 May 27.

Abstract

Perturbed neuronal calcium homeostasis is a prominent feature in Alzheimer's disease (AD). Mitochondria accumulate calcium ions (Ca(2+)) for cellular bioenergetic metabolism and suppression of mitochondrial motility within the cell. Excessive Ca(2+) uptake into mitochondria often leads to mitochondrial membrane permeabilization and induction of apoptosis. Ca(2+) is an interesting second messenger which can initiate both cellular life and death pathways in mitochondria. This review critically discusses the potential of manipulating mitochondrial Ca(2+) concentrations as a novel therapeutic opportunity for treating AD. This review also highlights the neuroprotective role of a number of currently available agents that modulate different mitochondrial Ca(2+) transport pathways. It is reasoned that these mitochondrial Ca(2+) modulators are most effective in combination with agents that increase the Ca(2+) buffering capacity of mitochondria. Modulation of mitochondrial Ca(2+) handling is a potential pharmacological target for future development of AD treatments.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / physiopathology
  • Alzheimer Disease / therapy*
  • Animals
  • Calcium Channel Blockers / pharmacology
  • Calcium Channel Blockers / therapeutic use
  • Calcium Signaling / drug effects*
  • Calcium Signaling / physiology
  • Calcium* / physiology
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use
  • Humans
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / physiology
  • Mitochondria / ultrastructure
  • Mitochondrial Membranes / drug effects*
  • Mitochondrial Membranes / physiology
  • Molecular Targeted Therapy
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Submitochondrial Particles / physiology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology

Substances

  • Calcium Channel Blockers
  • Cholinesterase Inhibitors
  • Neuroprotective Agents
  • Receptors, N-Methyl-D-Aspartate
  • Calcium