TY - JOUR
T1 - Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits
AU - Lacampagne, Alain
AU - Liu, Xiaoping
AU - Reiken, Steven
AU - Bussiere, Renaud
AU - Meli, Albano C.
AU - Lauritzen, Inger
AU - Teich, Andrew F.
AU - Zalk, Ran
AU - Saint, Nathalie
AU - Arancio, Ottavio
AU - Bauer, Charlotte
AU - Duprat, Fabrice
AU - Briggs, Clark A.
AU - Chakroborty, Shreaya
AU - Stutzmann, Grace E.
AU - Shelanski, Michael L.
AU - Checler, Frederic
AU - Chami, Mounia
AU - Marks, Andrew R.
N1 - Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
KW - Amyloid beta
KW - Calcium
KW - Oxidative stress
KW - PKA-dependent phosphorylation
KW - Ryanodine receptor 2
UR - http://www.scopus.com/inward/record.url?scp=85021109953&partnerID=8YFLogxK
U2 - 10.1007/s00401-017-1733-7
DO - 10.1007/s00401-017-1733-7
M3 - Article
AN - SCOPUS:85021109953
SN - 0001-6322
VL - 134
SP - 749
EP - 767
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 5
ER -