Involvement of presenilin holoprotein upregulation in calcium dyshomeostasis of Alzheimer's disease

Abstract

Mutations in presenilins (PS1 and PS2) account for the vast majority of early onset familial Alzheimer's disease cases. Beside the well investigated role of presenilins as the catalytic unit in γ-secretase complex, their involvement in regulation of intracellular calcium homeostasis has recently come into more focus of Alzheimer's disease research. Here we report that the overexpression of PS1 full-length holoprotein forms, in particular familial Alzheimer's disease-causing forms of PS1, result in significantly attenuated calcium release from thapsigargin- and bradykinin-sensitive stores. Interestingly, treatment of HEK293 cells with γ-secretase inhibitors also leads to decreased amount of calcium release from endoplasmic reticulum (ER) accompanying elevated PS1 holoprotein levels. Similarly, the knockdown of PEN-2 which is associated with deficient PS1 endoproteolysis and accumulation of its holoprotein form also leads to decreased ER calcium release. Notably, we detected enhanced PS1 holoprotein levels also in postmortem brains of patients carrying familial Alzheimer's disease PS1 mutations. Taken together, the conditions in which the amount of full length PS1 holoprotein is increased result in reduction of calcium release from ER. Based on these results, we propose that the disturbed ER calcium homeostasis mediated by the elevation of PS1 holoprotein levels may be a contributing factor to the pathogenesis of Alzheimer's disease.

Role of endoplasmic reticulum Ca2+ signaling in the pathogenesis of Alzheimer disease

“…As discussed in the recent review article (Bezprozvanny, 2013) these findings provide strong support to our hypothesis that presenilin holoprotein functions as ER calcium leak channel. Interestingly, Honarnejad et al (2013) recently reported that there is PS holoprotein upregulation in human AD brain samples, suggesting a possibility of compensatory upregulation of leak pathway in AD neurons in order to reduce ER Ca 2+ overload.…”

Attenuated presenilin‐1 endoproteolysis enhances store‐operated calcium currents in neuronal cells

“…The elevated PS1 holoprotein levels have been detected in postmortem brains of patients carrying familial Alzheimer's disease PS1 mutations, and the deficient PS1 endoproteolysis and the accumulation of full‐length PS1 holoprotein have been shown to result in significantly attenuated ER calcium release in Tg‐treated HEK293 cells (Honarnejad et al . ). In our model experiments with Neuro2a cells, an elevation in the PS1 holoprotein level was caused by pharmacological inhibition of PS1/γ‐secretase enzymatic activity.…”

“…Elevated PS1 holoprotein levels have been detected in postmortem brains of patients carrying familial Alzheimer's disease PS1 mutations (Honarnejad et al . ). The increased PS1 protein and mRNA levels have also been detected in the brain tissue of patients with sporadic AD (Borghi et al .…”

“…Deficient PS1 endoproteolysis and consequent accumulation of full‐length PS1 holoprotein result in significantly attenuated ER calcium release by Tg in HEK293 cells (Honarnejad et al . ). The observed effects on ER calcium have raised interest in the study of possible SOC entry disturbances as part of calcium homeostasis imbalance in neuronal cells under pathological conditions resulting in attenuated PS1 endoproteolysis.…”

“…In addition, an elevated PS1 holoprotein level has been shown to affect calcium release from ER in HEK cells (Honarnejad et al . ). The exact molecular mechanism as to how FAD PS1 mutations cause ER calcium dyshomeostasis is not fully resolved.…”