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

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DOIResolve DOI: http://doi.org/10.1074/jbc.M606736200
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TypeArticle
Journal titleJournal Of Biological Chemistry
ISSN00219258
Volume281
IssueOctober 50
Pages3844038447; # of pages: 8
SubjectAlzheimer Disease; amyloid beta protein; animals; base sequence; calcium/metabolism; DNA primers; neurons; peptide fragments
AbstractDisruption 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 postmortem 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 RNA directed 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.
Publication date
PublisherAmerican Society for Biochemistry and Molecular Biology
LanguageEnglish
AffiliationNational Research Council Canada; NRC Institute for Nutrisciences and Health
Peer reviewedYes
NPARC number9167108
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Record identifierb87e7e23-4061-4d4d-afc7-c768c298a8b5
Record created2009-10-03
Record modified2016-05-09
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