Aβ-induced synaptic impairments require CaMKII activity that is stimulated by indirect signaling events

Aβ bears homology to the CaMKII regulatory domain, and peptides derived from this domain can bind to CaMKII and disrupt the holoenzyme, suggesting that Aβ could have a similar effect. Notably, the CaMKII holoenzyme structure is required for a synaptic process that is impaired by Aβ and in turn impairs long-term potentiation (LTP) of synaptic strength: the stimulation-induced synaptic accumulation of CaMKII that is mediated by binding to the NMDA receptor subunit GluN2B. Furthermore, this Aβ-induced impairment is prevented by two CaMKII inhibitors that act by mechanisms that should also inhibit the putative Aβ binding to CaMKII. However, we did not find any evidence for a direct effect of Aβ on CaMKII: Aβ did not directly disrupt CaMKII holoenzymes, GluN2B binding, T286 autophosphorylation or kinase activity in vitro. Most importantly, in neurons, the Aβ-induced impairment of CaMKII synaptic accumulation was prevented by an ATP-competitive CaMKII inhibitor that would not interfere with the putative direct Aβ binding. Together, our results indicate that synaptic Aβ effects are not mediated by direct binding to CaMKII, but instead require CaMKII activation via indirect signaling events.