Up-regulation of the type 3 ryanodine receptor is neuroprotective in the TgCRND8 mouse model of Alzheimer's disease

Charlene Supnet, Charmaine Noonan, Kelly Richard, John Bradley, Michael Mayne

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

The cellular pathology of Alzheimer's disease is progressive and protracted leading eventually to considerable neuronal death. The underlying mechanisms of the pathology are complex but changes in the control of intracellular Ca 2+ are believed to contribute to the demise of neurons. In this study, we investigated the functional consequences of an increase in the expression of the type 3 isoform of the ryanodine receptor (RyR3). We found that although cortical neurons from TgCRND8 mice secreted significantly more amyloid beta protein and showed significantly increased RyR3 expression, they were no more sensitive to cell stress than non-transgenic neurons. Furthermore, despite increased intracellular Ca2+ release in response to ryanodine, we found that basal Ca2+, K+-evoked Ca2+ responses, and capacitative Ca2+ entry were no different in TgCRND8 neurons compared with non-transgenic neurons. Therefore, as RyR3 up-regulation did not affect neuronal health or global Ca2+ homeostasis, we investigated the effect of reducing RyR3 expression using small interfering RNA. Surprisingly, a reduction of RyR3 expression in TgCRND8, but not in non-transgenic, neurons increased neuronal death. These data reveal a new role for RyR3 and indicate a novel potential therapeutic target to delay or prevent the progression of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)356-365
Number of pages10
JournalJournal of Neurochemistry
Volume112
Issue number2
DOIs
StatePublished - Jan 1 2010

Keywords

  • Alzheimer's disease
  • Endoplasmic reticulum
  • Intracellular calcium
  • Neuroprotection
  • Ryanodine receptor
  • TgCRND8

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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