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J. Biol. Chem., Vol. 281, Issue 50, 38440-38447, December 15, 2006

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Amyloid--(1-42) Increases Ryanodine Receptor-3 Expression and Function in Neurons of TgCRND8 Mice^*

Charlene Supnet, Jeff Grant^¶1, Hong Kong, David Westaway^||, and Michael Mayne^¶**2

From the Institute for Nutrisciences and Health, National Research Council of Canada, Charlottetown, Prince Edward Island C1A 5T1, the Department of Biomedical Sciences, Atlantic Veterinary College/University of Prince Edward Island, Charlottetown, Prince Edward Island C1A 4P3, the ^¶Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba R3E 0T6, ^||Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario M5S 3H2, and ^**Division of Neurodegenerative Disorders, St. Boniface General Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada

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 postmortem hippocampal regions suggesting that RyR(s) are involved in AD pathogenesis. Here we report that extracellular amyloid-(A)-(1-42) specifically increased RyR-3, but not RyR-1 or RyR-2, gene expression in cortical neurons from C57Bl6 mice. Furthermore, endogenously produced A-(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 A-(1-42)-mediated changes in intracellular calcium homeostasis is regulated in part through a direct increase of RyR-3 expression and function.

Received for publication, July 14, 2006 , and in revised form, October 5, 2006.

^* This work was supported in part by the Manitoba Health Research Council, an industry award from the Alzheimer Society of Canada, Canadian Institute for Health Research, and AstraZeneca. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a graduate student fellowship from the Alzheimer Society of Canada.

² To whom correspondence should be addressed: Institute of Nutrisciences and Health, National Research Council of Canada, Rm. MO-02, 93 Mount Edward Rd., Charlottetown, Prince Edward Island C1A 5T1, Canada. Tel.: 902-566-7465; Fax: 902-569-4289; E-mail: michael.mayne{at}nrc.gc.ca.

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