Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons

Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PSI) gene. PS1 mutations may perturb cellula r Ca2+ homeostasis and thereby render neurons vulnerable to excitotoxicity and apoptosis. We now report that PC12 cells expressing PS1 mutations and p rimary hippocampal neurons from PS1 mutant knockin mice exhibit greatly inc reased levels of ryanodine receptors (RyR) and enhanced Ca2+ release follow ing stimulation with caffeine. Double-labeling immunostaining and co-immuno precipitation analyses indicate that PS1 and RyR are colocalized and intera ct physically, Caffeine treatment sensitizes neurons expressing mutant PS1 to apoptosis induced by amyloid beta-peptide, a neurotic peptide linked to the pathogenesis of AD. When taken together with recent evidence for altera tions in RyR in brains of AD patients, our data suggest that PS1 mutations may promote neuronal degeneration in AD by increasing transcription and tra nslation of RyR and altering functional properties of ryanodine-sensitive C a2+ pools.