Calcium Dyshomeostasis in Alzheimer’s Disease Pathogenesis

Abstract

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that is characterized by amyloid β-protein deposition in senile plaques, neurofibrillary tangles consisting of abnormally phosphorylated tau protein, and neuronal loss leading to cognitive decline and dementia. Despite extensive research, the exact mechanisms underlying AD remain unknown and effective treatment is not available. Many hypotheses have been proposed to explain AD pathophysiology; however, there is general consensus that the abnormal aggregation of the amyloid β peptide (Aβ) is the initial event triggering a pathogenic cascade of degenerating events in cholinergic neurons. The dysregulation of calcium homeostasis has been studied considerably to clarify the mechanisms of neurodegeneration induced by Aβ. Intracellular calcium acts as a second messenger and plays a key role in the regulation of neuronal functions, such as neural growth and differentiation, action potential, and synaptic plasticity. The calcium hypothesis of AD posits that activation of the amyloidogenic pathway affects neuronal Ca2+ homeostasis and the mechanisms responsible for learning and memory. Aβ can disrupt Ca2+ signaling through several mechanisms, by increasing the influx of Ca2+ from the extracellular space and by activating its release from intracellular stores. Here, we review the different molecular mechanisms and receptors involved in calcium dysregulation in AD and possible therapeutic strategies for improving the treatment.

Protection against Amyloid-β Oligomer Neurotoxicity by Small Molecules with Antioxidative Properties: Potential for the Prevention of Alzheimer’s Disease Dementia

“…Many in vitro and in vivo studies have shown that AβO exposure causes the production of reactive oxygen species (ROS), likely as a result of mitochondrial dysfunction. AβOs also induce Ca 2+ dyshomeostasis, not only in the cytosol but also in mitochondria [ 18 , 19 ]. Specifically, AβOs have been shown to increase mitochondrial Ca 2+ via the mitochondrial Ca 2+ unipolar complex [ 19 ].…”

Metals and Metal-Nanoparticles in Human Pathologies: From Exposure to Therapy

“…Calcium acts as a second intracellular messenger and plays a key role in the regulation of neuronal functions, namely neural growth and differentiation, action potential, and synaptic plasticity [70]. Calcium signaling is involved in neurotransmitter release, synaptic plasticity, gene expression, and other important neuronal functions [71].…”

Intracellular injection of brain extracts from Alzheimer’s disease patients trigger unregulated Ca2+ release from intracellular stores that hinders cellular bioenergetics

“…Progressive disruption of neuronal Ca 2+ homeostasis is one of the leading mechanisms of action of the amyloidogenic proteins Ab as the toxic species in the etiology of Alzheimer`s disease (AD) [1][2][3]. Increase in intracellular content of oligomeric Abs is believed to play a major role in the early phase of AD as their intracellular rise strongly correlates with the symptoms and have been proved to be predictive of cognitive status in AD affected patients [4][5][6].…”