Calcium Dyshomeostasis Drives Pathophysiology and Neuronal Demise in Age-Related Neurodegenerative Diseases

This review postulates that age-related neurodegeneration entails inappropriate activation of intrinsic pathways to enable brain plasticity through deregulated calcium (Ca(2+)) signalling. Ca(2+) in the cytosol comprises a versatile signal controlling neuronal cell physiology to accommodate adaptive structural and functional changes of neuronal networks (neuronal plasticity) and, as such, is essential for brain function. Although disease risk factors selectively affect different neuronal cell types across age-related neurodegenerative diseases (NDDs), these appear to have in common the ability to impair the specificity of the Ca(2+) signal. As a result, non-specific Ca(2+) signalling facilitates the development of intraneuronal pathophysiology shared by age-related NDDs, including mitochondrial dysfunction, elevated reactive oxygen species (ROS) levels, impaired proteostasis, and decreased axonal transport, leading to even more Ca(2+) dyshomeostasis. These core pathophysiological processes and elevated cytosolic Ca(2+) levels comprise a self-enforcing feedforward cycle inevitably spiralling toward high levels of cytosolic Ca(2+). The resultant elevated cytosolic Ca(2+) levels ultimately gear otherwise physiological effector pathways underlying plasticity toward neuronal demise. Ageing impacts mitochondrial function indiscriminately of the neuronal cell type and, therefore, contributes to the feedforward cycle of pathophysiology development seen in all age-related NDDs. From this perspective, therapeutic interventions to safely restore Ca(2+) homeostasis would mitigate the excessive activation of neuronal destruction pathways and, therefore, are expected to have promising neuroprotective potential.