Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease

Santo Gratteri,Salvatore Amoroso,Pasqualina Castaldo,Vincenzo Lariccia,Alessandra Matteucci,Maria Loredana Macrì,Guendalina Bastioli,Simona Magi,Marta Maiolino

doi:10.1155/2016/6701324

Abstract

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive neuronal loss. AD is associated with aberrant processing of the amyloid precursor protein, which leads to the deposition of amyloid-β plaques within the brain. Together with plaques deposition, the hyperphosphorylation of the microtubules associated protein tau and the formation of intraneuronal neurofibrillary tangles are a typical neuropathological feature in AD brains. Cellular dysfunctions involving specific subcellular compartments, such as mitochondria and endoplasmic reticulum (ER), are emerging as crucial players in the pathogenesis of AD, as well as increased oxidative stress and dysregulation of calcium homeostasis. Specifically, dysregulation of intracellular calcium homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Aberrant calcium signaling has been considered a phenomenon mainly related to the dysfunction of intracellular calcium stores, which can occur in both neuronal and nonneuronal cells. This review reports the most recent findings on cellular mechanisms involved in the pathogenesis of AD, with main focus on the control of calcium homeostasis at both cytosolic and mitochondrial level.

Highlights

Alzheimer’s Disease (AD) is the most common type of dementia affecting millions of people
The observed alterations in intracellular calcium homeostasis in neurons significantly contribute to the pathogenesis of AD, more recent findings suggest that calcium dysregulation occurring in other cell types that support neuronal activity may contribute to degenerative processes [86]
Dysregulation of intracellular calcium homeostasis has been suggested as a proximal cause of cellular dysfunction during AD, and in this context calcium imbalance has been considered a phenomenon mainly related to the dysfunction of subcellular organelles, such as mitochondria

Summary

Introduction

Alzheimer’s Disease (AD) is the most common type of dementia affecting millions of people. Three genetic mutations have been identified as being responsible for FAD They involve genes for amyloid precursor protein (APP) on chromosome 21 [10], presenilin 1 (PS1) on chromosome 14 [11], and presenilin 2 (PS2) on chromosome 1 [12]. It has been described that soluble Aβ globular oligomers can form along a new aggregation pathway independent of Aβ fibril formation These globular Aβ oligomers have been found in the brain of patients affected by AD and APP transgenic mice, and they bind to neurons and affect synaptic plasticity, as demonstrated by Barghorn and coworkers [18]. This review attempts to clarify connections between mitochondrial pathways impairment and the pathogenesis of AD, drawing attention to the calcium homeostasis deregulation as a potential consequence of mitochondrial function disturbance and to the proteins mainly involved in this process, such as the sodium-calcium exchanger (NCX)

Calcium and AD

Mitochondria and AD

Findings

Conclusions