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

Abstract

This review postulates that age-related neurodegeneration entails inappropriate activation of intrinsic pathways to enable brain plasticity through deregulated calcium (Ca²⁺) signalling. Ca²⁺ 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 Ca²⁺ signal. As a result, non-specific Ca²⁺ 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 Ca²⁺ dyshomeostasis. These core pathophysiological processes and elevated cytosolic Ca²⁺ levels comprise a self-enforcing feedforward cycle inevitably spiralling toward high levels of cytosolic Ca²⁺. The resultant elevated cytosolic Ca²⁺ 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 Ca²⁺ homeostasis would mitigate the excessive activation of neuronal destruction pathways and, therefore, are expected to have promising neuroprotective potential.

Keywords: Alzheimer’s disease; age-related neurodegeneration; calcium dyshomeostasis.

Figure 1

Schematic of the mechanisms underlying neuronal cell-type specific age-related neurodegeneration NDD risk factors impact directly or indirectly one or more core physiological processes in vulnerable neuronal populations predisposed to these risk factors: mitochondrial dysfunction, elevated ROS production, impaired proteostasis, decreased axonal trafficking, and calcium dyshomeostasis. Ageing is a risk factor that affects the pathophysiology indiscriminately of neuronal identity. These pathophysiological processes are engaged with cytosolic calcium in a vicious feedforward cycle, ultimately leading to excessive activation of Ca²⁺ effector pathways (Table 1). This cascade of events enables destruction and dysfunction of the vulnerable neuronal cell type, and consequently, associated neuronal cell type-specific neuropathology develops, leading to disease-specific symptoms. Green text indicates the most effective point of a therapeutic intervention entailing mitigation or prevention of an abnormal rise in Ca²⁺ in the cytosol. See text for more details.