Cell Reports
Volume 23, Issue 11, 12 June 2018, Pages 3137-3145
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Report
CaMKII Metaplasticity Drives Aβ Oligomer-Mediated Synaptotoxicity

https://doi.org/10.1016/j.celrep.2018.05.036Get rights and content
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Highlights

  • 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

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.

Keywords

CaMKII
oligomeric Aβ
NMDAR
GluN2B
AMPAR
Alzheimer’s disease
APP
dendritic spines
metaplasticity
long-term potentiation
LTP

Cited by (0)

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Present address: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, St. Lucia, QLD, Australia

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Lead Contact