Modulation of mitochondrial calcium as a pharmacological target for Alzheimer's disease.
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.
Hung
Clara Hiu-Ling
CH
Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
Ho
Yuen-Shan
YS
Chang
Raymond Chuen-Chung
RC
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D000818:Animals; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000502:physiology; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013367:Submitochondrial Particles / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D002121:Calcium Channel Blockers; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium