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Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits

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Abstract

The mechanisms underlying ryanodine receptor (RyR) dysfunction associated with Alzheimer disease (AD) are still not well understood. Here, we show that neuronal RyR2 channels undergo post-translational remodeling (PKA phosphorylation, oxidation, and nitrosylation) in brains of AD patients, and in two murine models of AD (3 × Tg-AD, APP +/− /PS1 +/−). RyR2 is depleted of calstabin2 (KFBP12.6) in the channel complex, resulting in endoplasmic reticular (ER) calcium (Ca2+) leak. RyR-mediated ER Ca2+ leak activates Ca2+-dependent signaling pathways, contributing to AD pathogenesis. Pharmacological (using a novel RyR stabilizing drug Rycal) or genetic rescue of the RyR2-mediated intracellular Ca2+ leak improved synaptic plasticity, normalized behavioral and cognitive functions and reduced Aβ load. Genetically altered mice with congenitally leaky RyR2 exhibited premature and severe defects in synaptic plasticity, behavior and cognitive function. These data provide a mechanism underlying leaky RyR2 channels, which could be considered as potential AD therapeutic targets.

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Acknowledgements

This work was supported by NHLBI-R01HL061503 (ARM), NHLBI-R01HL102040 (ARM), NIAMS-R01AR060037 (ARM), NIH T32 HL120826 (ARM), NINDS-R25NS076445 (ARM), the Fondation Leducq and a generous donation from Carol Stix (ARM); Inserm, Philipp Foundation and Schaefer Award from Columbia University (AL); LECMA (Ligue Européenne Contre la Maladie d’Alzheimer) (MC); LABEX (Excellence Laboratory, Program Investment for the Future), DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer’s disease) (FC), the University Hospital Federation (FHU)-OncoAge (FC), the Fondation Pompidou (FC); NIA-RO1AG030205 (GES). The authors thank Steven Siegelbaum, Eric Kandel and Richard Axel for helpful discussions and comments on the paper and Valerie Scheuermann for preliminary biochemical experiments.

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Author notes

  1. Alain Lacampagne, ** Liu and Steven Reiken contributed equally to this work and are co-first authors.

    Frederic Checler, Mounia Chami and Andrew R. Marks contributed equally to this work and are co-senior authors.

Authors and Affiliations

  1. Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA

    ** Liu, Steven Reiken, Ran Zalk & Andrew R. Marks

  2. INSERM U1046, CNRS UMR9214/LIA1185, Université de Montpellier, CHRU Montpellier, Montpellier, France

    Alain Lacampagne, Albano C. Meli & Nathalie Saint

  3. Université Côte d’Azur, INSERM, CNRS, IPMC, Laboratory of Excellence DistALZ, 06560, Sophia-Antipolis, Valbonne, France

    Renaud Bussiere, Inger Lauritzen, Charlotte Bauer, Fabrice Duprat, Frederic Checler & Mounia Chami

  4. Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA

    Andrew F. Teich, Ottavio Arancio & Michael L. Shelanski

  5. Department of Neuroscience, Rosalind Franklin University/Chicago Medical School, North Chicago, IL, 60064, USA

    Clark A. Briggs, Shreaya Chakroborty & Grace E. Stutzmann

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  1. Alain Lacampagne
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Contributions

ARM and MC independently conceived the study. XL, MC, FC, AL and ARM designed the studies, analyzed data and wrote the manuscript. XL conducted studies on APP +/− /PS1 +/−, RyR2-S2808D +/+, RyR2-S2808A +/+ and RyR2-S2808A +/+ × APP +/− /PS1 +/− mouse colonies. SR designed and conducted biochemistry assays of RyR2. MC, AL, RB, IL, CB and FD conducted studies on the 3 × Tg-AD mice. AM, NS and AL designed and conducted RyR2 single-channel analyses. AFT conducted the immunohistochemistry experiments on APP +/− /PS1 +/− and RyR2-S2808A +/+ × APP +/− /PS1 +/− mice and analyzed the data. CAB, SC and GES designed, conducted and performed patch-clamp Ca2+ imaging and sEPSP experiments and analyzed the data. OA analyzed the electrophysiological recordings and behavioral studies. MS designed the experiments, analyzed data and edited the manuscript.

Corresponding authors

Correspondence to Mounia Chami or Andrew R. Marks.

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Ethical approval

All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

In vivo experiments were performed in accordance with the regulations of the Institutional Animal Care and Use Committee of Columbia University (APP+/−/PS1+/−, RyR2-S2808A +/+ , and RyR2-S2808D +/+ mice) and with the guidelines established by the European Community Council (Directive of November 24th, 1986) and approved by the Nice University Animal care and use Committee and the National Council on animal care of the Ministry of Health (Project No: NCE/2013-152) (3 × Tg-AD mice).

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical studies.

Informed consent

Informed consent for tissue donation for research was obtained by the brain banks under their approval procedures.

Conflict of interest

ARM is a board member and owns shares in ARMGO Pharma Inc., which is targeting RyR channels for therapeutic purposes.

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Lacampagne, A., Liu, X., Reiken, S. et al. Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits. Acta Neuropathol 134, 749–767 (2017). https://doi.org/10.1007/s00401-017-1733-7

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  • DOI: https://doi.org/10.1007/s00401-017-1733-7

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