Presenilin-2 mutations modulate amplitude and kinetics of inositol 1,4,5-trisphosphate-mediated calcium signals

Mutations in the two presenilin genes (PS1, PS2) account for the majority o f early-onset familial Alzheimer's disease (FAD) cases. Converging evidence from a variety of experimental systems, including fibroblasts from FAD pat ients and transgenic animals, indicates that PSI mutations modulate intrace llular calcium signaling pathways. Despite the potential relevance of these changes to the pathogenesis of FAD, a comparable effect for PS2 has not ye t been demonstrated experimentally. We examined the effects of wild-type PS 2, and both of the identified FAD mutations in PS2, on intracellular calciu m signaling in Xenopus oocytes. Inositol 1,4,5-trisphosphate (IP3)-evoked c alcium signals were significantly potentiated in cells expressing either of the PS2 mutations relative to wild-type PS2-expressing cells and controls. Decay rates of calcium signals were also significantly accelerated in muta nt PS2-expressing cells in a manner dependent upon IF, concentration, The f inding that mutations in both PS1 and PS2 modulate intracellular calcium si gnaling suggests that these disturbances may represent a common pathogenic mechanism of presenilin-associated FAD.