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.