Mitochondrial Calcium Deregulation in the Mechanism of Beta-Amyloid and Tau Pathology

Aggregation and deposition of β-amyloid and/or tau protein are the key neuropathological features in neurodegenerative disorders such as Alzheimer’s disease (AD) and other tauopathies including frontotemporal dementia (FTD). The interaction between oxidative stress, mitochondrial dysfunction and the impairment of calcium ions (Ca(2+)) homeostasis induced by misfolded tau and β-amyloid plays an important role in the progressive neuronal loss occurring in specific areas of the brain. In addition to the control of bioenergetics and ROS production, mitochondria are fine regulators of the cytosolic Ca(2+) homeostasis that induce vital signalling mechanisms in excitable cells such as neurons. Impairment in the mitochondrial Ca(2+) uptake through the mitochondrial Ca(2+) uniporter (MCU) or release through the Na(+)/Ca(2+) exchanger may lead to mitochondrial Ca(2+) overload and opening of the permeability transition pore inducing neuronal death. Recent evidence suggests an important role for these mechanisms as the underlying causes for neuronal death in β-amyloid and tau pathology. The present review will focus on the mechanisms that lead to cytosolic and especially mitochondrial Ca(2+) disturbances occurring in AD and tau-induced FTD, and propose possible therapeutic interventions for these disorders.