Loading…

CaMKII Metaplasticity Drives Aβ Oligomer-Mediated Synaptotoxicity

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...

Full description

Saved in:
Bibliographic Details
Published in:Cell reports (Cambridge) 2018-06, Vol.23 (11), p.3137-3145
Main Authors: Opazo, Patricio, Viana da Silva, Silvia, Carta, Mario, Breillat, Christelle, Coultrap, Steven J., Grillo-Bosch, Dolors, Sainlos, Matthieu, Coussen, Françoise, Bayer, K. Ulrich, Mulle, Christophe, Choquet, Daniel
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. [Display omitted] •Oligomeric Aβ triggers the non-autonomous activation of CaMKII•Oligomeric Aβ prevents the activation of CaMKII by subsequent rounds of plasticity•CaMKII activation leads to deficits in long-term potentiation and dendritic spine loss•CaMKII drives synaptotoxicity via the destabilization of synaptic AMPA receptors Opazo et al. show that oligomeric and synaptotoxic forms of the Aβ peptide trigger the rapid activation of CaMKII throughout the neuron. They find that aberrant CaMKII activation leads to deficits in long-term potentiation and ultimately synaptic loss via the destabilization of AMPA receptors.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2018.05.036