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

Abstract

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 (Ca2+) 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 Ca2+ homeostasis that induce vital signalling mechanisms in excitable cells such as neurons. Impairment in the mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) or release through the Na+/Ca2+ exchanger may lead to mitochondrial Ca2+ 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 Ca2+ disturbances occurring in AD and tau-induced FTD, and propose possible therapeutic interventions for these disorders.

Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches

“…In this Special Issue in Cells , six reviews address the newest results and advances in calcium signalling deregulation mechanisms in AD, how they are linked to other molecular players involved in AD pathogenesis, and the potential therapeutic approaches to correct calcium alterations to treat AD [ 23 , 24 , 25 , 26 , 27 , 28 ].…”

“…In addition to synaptic plasticity deficits, calcium dyshomeostasis has a profound effect on the function of cell organelles, including ER and mitochondria, both of which play an important role in maintaining cellular and synaptic function. These specific items were discussed in our review [ 23 ] and in that by Noemi Esteras and Andrey Y. Abramov [ 25 ], respectively.…”

“…The review by Noemi Esteras and Andrey Y. Abramov specifically describes the mechanisms underlying mitochondrial calcium deregulation linked to Aβ and tau pathologies [ 25 ]. They first depict the basis of physiological mitochondrial calcium homeostasis and then describe the cytosolic and mitochondrial calcium homeostasis impairments in AD and in tauopathies (neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain) [ 25 ]. The authors specifically discuss the molecular mechanisms underlying mitochondrial calcium disturbances and expose complementary scenarios linking the deleterious mitochondria calcium overload to neuronal death [ 25 ].…”

“…They first depict the basis of physiological mitochondrial calcium homeostasis and then describe the cytosolic and mitochondrial calcium homeostasis impairments in AD and in tauopathies (neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain) [ 25 ]. The authors specifically discuss the molecular mechanisms underlying mitochondrial calcium disturbances and expose complementary scenarios linking the deleterious mitochondria calcium overload to neuronal death [ 25 ]. These mechanisms include the alteration of the expression of mitochondrial calcium-related proteins and of ER–mitochondria interactions, and also the impairment of mitochondrial calcium efflux, and mitochondrial permeability transition pore opening.…”

“…These mechanisms include the alteration of the expression of mitochondrial calcium-related proteins and of ER–mitochondria interactions, and also the impairment of mitochondrial calcium efflux, and mitochondrial permeability transition pore opening. These mechanisms appear to act in concert in the process of neurodegeneration in AD and tauopathies [ 25 ].…”