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 (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.
Chan
S L
SL
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington, Kentucky 40536, USA.
Mayne
M
M
Holden
C P
CP
Geiger
J D
JD
Mattson
M P
MP
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D006624:Hippocampus / Q000166:cytology; D006706:Homeostasis / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D053764:Presenilin-1; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D014162:Transfection
D008565:Membrane Proteins; D053764:Presenilin-1; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D002118:Calcium