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.
Highlights
Alzheimer’s disease (AD) is the most common cause of age-related neurodegenerative disease, which is characterized by progressive memory loss, cognitive dysfunction, language disorders, and personality changes [1]
The effects of amyloid β peptide (Aβ) on Nmethyl D-aspartate receptor (NMDAR) have attracted considerable interest as these ligand-gated channels are involved in synaptic plasticity and LTP [184]
Concluding Remarks Many studies have revealed that the perturbation of Ca2+ homeostasis is an early event in the cascade of neuronal alterations underlying the cytotoxicity induced by misfolded Aβ aggregates and hyperphosphorylated tau
Summary
Alzheimer’s disease (AD) is the most common cause of age-related neurodegenerative disease, which is characterized by progressive memory loss, cognitive dysfunction, language disorders, and personality changes [1]. The amyloid cascade was considered for a long time as a dominant model for AD pathogenesis [10] According to this hypothesis, the starting event in AD is the aggregation and subsequent deposition of the Aβ peptide in the brain [20,21], resulting in the hyperphosphorylation of tau into NFTs and, the degeneration of neurons. A dominant theory for the incidence of AD is the “amyloid hypothesis”, which describes a complex sequence of pathogenic events responsible for neurodegeneration [55,56,57,58,59,60] According to this hypothesis, the aberrant accumulation of the Aβ peptide, following the amyloidogenic processing of the APP, results in the production of cytotoxic complexes and its deposition in various brain areas. Neither the amyloid nor tau hypotheses are sufficient to explain all the pathological mechanisms responsible for AD pathogenesis [25,98], but rather a unique theory taking into account the synergistic effects of both would explain many pathogenic processes occurring during AD progression
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