Amyloid-β-(1- 42) increases ryanodine receptor-3 expression and function in neurons of TgCRND8 mice

Charlene Supnet, Jeff Grant, Hong Kong, David Westaway, Michael Mayne

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Disruption of intracellular calcium homeostasis precedes the neurodegeneration that occurs in Alzheimer disease (AD). Of the many neuronal calcium-regulating proteins, we focused on endoplasmic reticulum (ER)-resident ryanodine receptors (RyRs) because they are increased in the hippocampus of mice expressing mutant presenilin-1 and are associated with neurotoxicity. Others have observed that ryanodine binding is elevated in human post-mortem hippocampal regions suggesting that RyR(s) are involved in AD pathogenesis. Here we report that extracellular amyloid-β(Aβ)-(1-42) specifically increased RyR-3, but not RyR-1 or RyR-2, gene expression in cortical neurons from C57Bl6 mice. Furthermore, endogenously produced Aβ-(1-42) increased RyR-3 mRNA and protein in cortical neurons from transgenic (Tg)CRND8 mice, a mouse model of AD. Increased RyR-3 mRNA and protein was also observed in brain tissue from 4- to 4.5-month-old Tg animals compared with non-Tg littermate controls. In experiments performed in nominal extracellular calcium, neurons from Tg mice had significant increases in intracellular calcium following ryanodine or glutamate treatment compared with littermate controls, which was abolished by treatment with small interfering RNAdirected to RyR-3, indicating that the higher levels of calcium originated from RyR-3-regulated stores. Taken together, these observations suggest that Aβ-(1-42)-mediated changes in intracellular calcium homeostasis is regulated in part through a direct increase of RyR-3 expression and function.

Original languageEnglish (US)
Pages (from-to)38440-38447
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number50
DOIs
StatePublished - Dec 15 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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