CaMKII Metaplasticity Drives Aβ Oligomer-Mediated Synaptotoxicity
Cell Reports. 2018-06-01; 23(11): 3137-3145
DOI: 10.1016/j.celrep.2018.05.036
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1. Cell Rep. 2018 Jun 12;23(11):3137-3145. doi: 10.1016/j.celrep.2018.05.036.
CaMKII Metaplasticity Drives Aβ Oligomer-Mediated Synaptotoxicity.
Opazo P(1), Viana da Silva S(2), Carta M(2), Breillat C(2), Coultrap SJ(3),
Grillo-Bosch D(2), Sainlos M(2), Coussen F(2), Bayer KU(3), Mulle C(2), Choquet
D(4).
Author information:
(1)Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR
5297, 33000 Bordeaux, France; CNRS, Interdisciplinary Institute for Neuroscience,
UMR 5297, 33000 Bordeaux, France. Electronic address: .
(2)Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR
5297, 33000 Bordeaux, France; CNRS, Interdisciplinary Institute for Neuroscience,
UMR 5297, 33000 Bordeaux, France.
(3)Department of Pharmacology, Anschutz Medical Campus, University of Colorado
School of Medicine, Aurora, CO 80045, USA.
(4)Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR
5297, 33000 Bordeaux, France; CNRS, Interdisciplinary Institute for Neuroscience,
UMR 5297, 33000 Bordeaux, France; Bordeaux Imaging Center, UMS 3420 CNRS,
Université de Bordeaux, US4 INSERM, 33000 Bordeaux, France. Electronic address:
.
Alzheimer’s disease (AD) is emerging as a synaptopathology driven by
metaplasticity. Indeed, reminiscent of metaplasticity, oligomeric forms of the
amyloid-β peptide (oAβ) prevent induction of long-term potentiation (LTP) via the
prior activation of GluN2B-containing NMDA receptors (NMDARs). However, the
downstream Ca2+-dependent signaling molecules that mediate aberrant
metaplasticity are unknown. In this study, we show that oAβ promotes the
activation of Ca2+/calmodulin-dependent kinase II (CaMKII) via GluN2B-containing
NMDARs. Importantly, we find that CaMKII inhibition rescues both the LTP
impairment and the dendritic spine loss mediated by oAβ. Mechanistically
resembling metaplasticity, oAβ prevents subsequent rounds of plasticity from
inducing CaMKII T286 autophosphorylation, as well as the associated anchoring and
accumulation of synaptic AMPA receptors (AMPARs). Finally, prolonged oAβ
treatment-induced CaMKII misactivation leads to dendritic spine loss via the
destabilization of surface AMPARs. Thus, our study demonstrates that oAβ engages
synaptic metaplasticity via aberrant CaMKII activation.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2018.05.036
PMID: 29898386