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 (Ca2+) for cellular bioenergetic metabolism and suppression of mitochondrial motility within the cell. Excessive Ca2+ uptake into mitochondria often leads to mitochondrial membrane permeabilization and induction of apoptosis. Ca2+ 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 Ca2+ 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 Ca2+ transport pathways. It is reasoned that these mitochondrial Ca2+ modulators are most effective in combination with agents that increase the Ca2+ buffering capacity of mitochondria. Modulation of mitochondrial Ca2+ handling is a potential pharmacological target for future development of AD treatments.