Alzheimer's presenilin-1 mutation potentiates inositol 1,4,5-trisphosphate-mediated calcium signaling in Xenopus oocytes

Perturbations in intracellular Ca2+ signaling may represent one mechanism u nderlying Alzheimer's disease (AD). The presenilin-1 gene (PS1), associated with the majority of early onset familial AD cases, has been implicated in this signaling pathway. Here we used the Xenopus oocyte expression system to investigate in greater detail the role of PS1 in intracellular Ca2+ sign aling pathways. Treatment of cells expressing wild-type PSI with a cell sur face receptor agonist to stimulate the phosphoinositide second messenger pa thway evoked Ca2+-activated Cl- currents that were significantly potentiate d relative to controls. To determine which elements of the signal transduct ion pathway are responsible for the potentiation, we used photolysis of cag ed inositol 1,4,5-trisphosphate (IP3) and fluorescent Ca2+ imaging to demon strate that PSI potentiates IP3-mediated release of Ca2+ from internal stor es. We show that an AD-linked mutation produces a potentiation in Ca2+ sign aling that is significantly greater than that observed for wild-type PSI an d that cannot be attributed to differences in protein expression levels. Ou r findings support a role for PS1 in modulating IP,-mediated Ca2+ liberatio n and suggest that one pathophysiological mechanism by which PS1 mutations contribute to AD neurodegeneration may involve perturbations of this functi on.