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CaMKII Metaplasticity Drives Aβ Oligomer-Mediated Synaptotoxicity
Patricio Opazo1, Silvia Viana da Silva1, Mario Carta1
1Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France; CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France.
Cell Reports
|June 14, 2018
Summary
Oligomeric amyloid-β (oAβ) in Alzheimer's disease disrupts synaptic plasticity by activating CaMKII. Inhibiting CaMKII restores long-term potentiation and prevents dendritic spine loss, revealing a key mechanism in AD synaptopathology.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Alzheimer's disease (AD) is increasingly recognized as a synaptopathology.
- Metaplasticity, a change in the rules of plasticity, is implicated in AD.
- Oligomeric amyloid-β (oAβ) impairs long-term potentiation (LTP) through GluN2B-containing NMDA receptors (NMDARs), but downstream effectors are unknown.
Purpose of the Study:
- To identify Ca2+-dependent signaling molecules mediating oAβ-induced aberrant metaplasticity.
- To investigate the role of Ca2+/calmodulin-dependent kinase II (CaMKII) in oAβ-induced synaptic dysfunction.
Main Methods:
- Investigated oAβ effects on NMDARs and CaMKII activation.
- Utilized CaMKII inhibition to assess its role in LTP and dendritic spine morphology.
- Examined CaMKII autophosphorylation and AMPA receptor dynamics.
Main Results:
- oAβ activates CaMKII via GluN2B-containing NMDARs.
- CaMKII inhibition rescued LTP impairment and dendritic spine loss caused by oAβ.
- oAβ disrupted CaMKII T286 autophosphorylation and AMPA receptor anchoring.
- CaMKII misactivation led to dendritic spine loss by destabilizing surface AMPA receptors.
Conclusions:
- oAβ induces synaptic metaplasticity through aberrant CaMKII activation.
- CaMKII is a critical mediator of oAβ-induced synaptic dysfunction in Alzheimer's disease.
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