Abstract
Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. PS1 mutations may perturb cellular Ca(2+) homeostasis and thereby render neurons vulnerable to excitotoxicity and apoptosis. We now report that PC12 cells expressing PS1 mutations and primary hippocampal neurons from PS1 mutant knockin mice exhibit greatly increased levels of ryanodine receptors (RyR) and enhanced Ca(2+) release following stimulation with caffeine. Double-labeling immunostaining and co-immunoprecipitation analyses indicate that PS1 and RyR are colocalized and interact 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 alterations in RyR in brains of AD patients, our data suggest that PS1 mutations may promote neuronal degeneration in AD by increasing transcription and translation of RyR and altering functional properties of ryanodine-sensitive Ca(2+) pools.
Highlights
Many cases of early-onset inherited Alzheimer’s disease (AD) are caused by mutations in the presenilin-1 (PS1) gene
Western blot analysis showed that levels of ryanodine receptors (RyR) type 3 protein were increased 7–10-fold in PC12 cell clones overexpressing mutant PS1 compared with clones overexpressing wild-type PS1 and vector-transfected control clones (Fig. 1C)
We found that levels of type 3 RyR are greatly increased in PC12 cells overexpressing mutant human PS1, and in brain tissue in knockin mice that express mutant PS1 at normal levels
Summary
18195–18200, 2000 Printed in U.S.A. Presenilin-1 Mutations Increase Levels of Ryanodine Receptors and Calcium Release in PC12 Cells and Cortical Neurons*. We report that PC12 cells expressing PS1 mutations and primary hippocampal neurons from PS1 mutant knockin mice exhibit greatly increased levels of ryanodine receptors (RyR) and enhanced Ca2؉ release following stimulation with caffeine. Hippocampal neurons from PS1 mutant knockin mice exhibit increased vulnerability to excitotoxicity, which is associated with enhanced elevations of intracellular Ca2ϩ levels [13]. ER contains two main types of Ca2ϩ release channels, the inositol 1,4,5-trisphosphate receptors (IP3R, ϳ300 kDa) and the ryanodine receptors (RyR,ϳ565 kDa), each represented by three different isoforms with similar structural properties [17]. The increased level of RyR is associated with enhanced Ca2ϩ responses to caffeine and increased neuronal vulnerability to excitotoxicity and apoptosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
