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

Sic L. Chan, Michael Mayne, Clark P. Holden, Jonathan D. Geiger, Mark P. Mattson

Research output: Contribution to journalArticle

233 Citations (Scopus)

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 Ca2+ homeostasis and thereby render neurons vulnerable to excitotoxicity and apoptosis. We now report that PC12 cells expressing PS1 mutations and primary hippocampal neurons from PSI mutant knockin mice exhibit greatly increased levels of ryanodine receptors (RyR) and enhanced Ca2+ 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 β-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 Ca2+ pools.

Original languageEnglish (US)
Pages (from-to)18195-18200
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number24
DOIs
StatePublished - Jun 16 2000

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Presenilin-1
Ryanodine Receptor Calcium Release Channel
PC12 Cells
Neurons
Calcium
Mutation
Alzheimer Disease
Caffeine
Apoptosis
Ryanodine
Peptides
Brain Diseases
Transcription
Immunoprecipitation
Amyloid
Labeling
Brain
Homeostasis
Genes
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. / Chan, Sic L.; Mayne, Michael; Holden, Clark P.; Geiger, Jonathan D.; Mattson, Mark P.

In: Journal of Biological Chemistry, Vol. 275, No. 24, 16.06.2000, p. 18195-18200.

Research output: Contribution to journalArticle

Chan, Sic L. ; Mayne, Michael ; Holden, Clark P. ; Geiger, Jonathan D. ; Mattson, Mark P. / Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 24. pp. 18195-18200.
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