Role of Ca2+ signaling in mitochondrial dysfunction as a basis of neurodegeneration in early-onset familial Alzheimer’s disease

Abstract

Familial Alzheimer’s disease (FAD) is characterized by autosomal-dominant heritability and early onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD. The etiology of AD is currently unknown, however exaggerated intracellular Ca2+ signaling may be a major contributing factor in early and late stages of the disease. Many PS1 mutations affect intracellular Ca2+ homeostasis, although the molecular details are still debated. Altered Ca2+ signaling is observed early in the development of the disease, long before the onset of measurable histopathology or cognitive deficits. One proposed molecular mechanism underlying exaggerated Ca2+ signaling is mediated by Ca2+ release from the endoplasmic reticulum (ER) through inositol 1,4,5-trisphosphate receptors (InsP3R). In FAD, the higher open probability of the InsP3R caused by PS mutations is predicted to lead to a significant increase in the Ca2+ microdomain concentration near the Ca2+ release channels and its spatial extent. To date, the involvement of exaggerated Ca2+ signaling in FAD on mitochondrial function has been evaluated only theoretically. Therefore, we proposed to investigate the role of InsP3R-mediated exaggerated Ca2+ signals on mitochondrial function in the context of FAD. Hypothesis: FAD-PS1 mutations enhance Ca2+ transfer between the ER and mitochondria inducing mitochondrial malfunction that leads to impaired cell function and death. We determined the role of Ca2+ dysregulation mediated by InsP3R-PS1 mutant interaction on mitochondrial function using two different in vitro cell models of FAD. Our findings, support our working hypothesis that cells expressing mutant PS1 are subjected to elevated mitochondrial Ca2+ levels, due to an exaggerated ER Ca2+ leak through the InsP3R, a decrease of mitochondrial Ca2+ extrusion capacity by the Na+ /Ca2+ exchanger as a result of decreased expression of NCLX and an increase in reactive oxygen species (ROS) production. These features may explain the increased vulnerability and eventual death of these cells due to progressive mitochondrial dysfunction, promoting a pathological cycle essential to disease progression.