Amyloid β production is regulated by β2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor

Renaud Bussiere; Alain Lacampagne; Steven Reiken; Xiaoping Liu; Valerie Scheuerman; Ran Zalk; Cécile Martin; Frederic Checler; Andrew R. Marks; Mounia Chami

doi:10.1074/jbc.M116.743070

Amyloid β production is regulated by β2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor

From the ^‡Université Côte d'Azur, CNRS, IPMC, France, “Labex Distalz,” 660 route des Lucioles, 06560 Sophia-Antipolis, Valbonne, France,
^§INSERM U1046, CNRS UMR9214, CNRS LIA1185, Université de Montpellier, CHRU Montpellier, 34295 Montpellier, France, and
^¶Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, New York 10032

↵3 To whom correspondence may be addressed. Tel.: 212-851-5348; Fax: 212-851-5346; E-mail: arm42{at}columbia.edu.
↵4 To whom correspondence may be addressed. Tel.: 33-493953457; Fax: 33-493953408; E-mail: mchami{at}ipmc.cnrs.fr.

Edited by Paul E. Fraser

Abstract

Alteration of ryanodine receptor (RyR)-mediated calcium (Ca²⁺) signaling has been reported in Alzheimer disease (AD) models. However, the molecular mechanisms underlying altered RyR-mediated intracellular Ca²⁺ release in AD remain to be fully elucidated. We report here that RyR2 undergoes post-translational modifications (phosphorylation, oxidation, and nitrosylation) in SH-SY5Y neuroblastoma cells expressing the β-amyloid precursor protein (βAPP) harboring the familial double Swedish mutations (APPswe). RyR2 macromolecular complex remodeling, characterized by depletion of the regulatory protein calstabin2, resulted in increased cytosolic Ca²⁺ levels and mitochondrial oxidative stress. We also report a functional interplay between amyloid β (Aβ), β-adrenergic signaling, and altered Ca²⁺ signaling via leaky RyR2 channels. Thus, post-translational modifications of RyR occur downstream of Aβ through a β2-adrenergic signaling cascade that activates PKA. RyR2 remodeling in turn enhances βAPP processing. Importantly, pharmacological stabilization of the binding of calstabin2 to RyR2 channels, which prevents Ca²⁺ leakage, or blocking the β2-adrenergic signaling cascade reduced βAPP processing and the production of Aβ in APPswe-expressing SH-SY5Y cells. We conclude that targeting RyR-mediated Ca²⁺ leakage may be a therapeutic approach to treat AD.

Footnotes

↵1 These authors should be considered as co-first authors.
↵2 These authors should be considered as co-senior authors.
This work was supported by National Institutes of Health Grants R01HL061503 (NHLBI; to A. R. M.), R01HL102040 (NHLBI; to A. R. M.), R01AR060037 (NIAMS; to A. R. M.), NIH T32 HL120826 (to A. R. M.), and R25NS076445 (NINDS; to A.R.M). This work was also supported by Fondation Leducq and a generous donation from Carol Stix (A. R. M.) and grants from INSERM, the Philippe Foundation, and a Schaefer Award from Columbia University (to A. L.), LECMA (Ligue Européenne Contre la Maladie d'Alzheimer) (to M. C.), LABEX (Laboratory of excellence, program investment for the future), DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer's disease) (to F. C.), and Hospital-University Federation (FHU OncoAge) (to F. C.). A. R. M. is a board member and owns shares in ARMGO Pharma Inc., which is targeting RyR channels for therapeutic purposes. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
This article contains supplemental Figs. 1.