CaMKII Metaplasticity Drives Aβ Oligomer-Mediated Synaptotoxicity

Abstract

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