Cytosolic calcium: Judge, jury and executioner of neurodegeneration in Alzheimer's disease and beyond

Abstract

This review discusses the driving principles that may underlie neurodegeneration in dementia, represented most dominantly by Alzheimer's disease (AD). While a myriad of different disease risk factors contribute to AD, these ultimately converge to a common disease outcome. Based on decades of research, a picture emerges where upstream risk factors combine in a feedforward pathophysiological cycle, culminating in a rise of cytosolic calcium concentration ([Ca2+]c) that triggers neurodegeneration. In this framework, positive AD risk factors entail conditions, characteristics, or lifestyles that initiate or accelerate self‐reinforcing cycles of pathophysiology, whereas negative risk factors or therapeutic interventions, particularly those mitigating elevated [Ca2+]c, oppose these effects and therefore have neuroprotective potential.

RNA G-quadruplexes and calcium ions synergistically induce Tau phase transitionin vitro

“…Persistent and excessive Ca 2+ entry in neurons could be a major factor in the development of neurodegeneration, including tauopathies [22, 23]. In addition, Tau aggregation is facilitated by divalent cations, including Ca 2+ in vitro [24, 25].…”

Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer’s disease

“…ReS19-T not only protects against acute Ab/tau-induced neurotoxicity but also mitigates the development of Ab and tau pathology. This implies the existence of a self-amplifying loop between elevated [Ca 2+ ] cyto and Ab/tau pathology (18). By lowering [Ca 2+ ] cyto , ReS19-T disrupts this harmful cycle rapidly and efficiently.…”

“…In diseased neurons, elevated resting [Ca 2+ ] cyto contributes to the development of AD pathology, including the production of pathological amyloid-b (Ab) and tau species (11)(12)(13)(14). Reciprocally, AD pathological changes cause an elevation in resting [Ca 2+ ] cyto , which triggers a program of neurodegeneration initiated by synaptic disruption and culminating with the activation of neuronal death pathways (15)(16)(17)(18). This suggests that deregulated [Ca 2+ ] cyto fuels a self-reinforcing amplification of AD pathobiology, ultimately causing neuronal demise.…”

Protein Biomarkers Shared by Multiple Neurodegenerative Diseases Are Calmodulin-Binding Proteins Offering Novel and Potentially Universal Therapeutic Targets

“…An early, possibly initiating, event in most, if not all, neurodegenerative diseases is calcium dysregulation. The critical, uncontrolled increase in calcium levels and the disruption of downstream calcium signaling has been well studied in AD and HD [11][12][13][14]. In PD, calcium dysregulation is an early event and subsequent αSyn aggregation feeds back to augment calcium dyshomeostasis, further disrupting calcium signal transduction and CaM-mediated events [15][16][17].…”