Subcellular mechanisms of presenilin-mediated enhancement of calcium signaling

Mutations in presenilin-1 (PS1), the leading cause of early-onset, autosoma l-dominant familial Alzheimer's disease (FAD), enhance calcium signaling me diated by inositol 1,4,5-trisphosphate (IP3). To elucidate the subcellular mechanisms underlying this enhancement, we used high resolution line-scanni ng confocal microscopy to image elementary calcium release events ("puffs") in Xenopus oocytes expressing wild-type or mutant PS1. Here we report that mutant pal-rendered puffs more sensitive to IP3 and increased both the mag nitude and the rate of calcium release during each event. These effects wer e not attributable to quantitative changes in the levels of IP3 receptors o r their distribution on the ER, but were instead associated with an abnorma l elevation of ER calcium stores. Together, our results suggest that the ef fects of mutant pal on calcium signaling are manifested predominantly at th e level of the regulation of calcium stores rather than via perturbations i n the numbers or activity of IP3-activated calcium release channels. (C) 20 01 Academic Press.