摘要：SummaryAβ bears homology to the CaMKII regulatory domain, and peptides derived from this domain can bind and disrupt the CaMKII holoenzyme, suggesting that Aβ could have a similar effect. Notably, Aβ impairs the synaptic CaMKII accumulation that is mediated by GluN2B binding, which requires CaMKII assembly into holoenzymes. Furthermore, this Aβ-induced impairment is prevented by CaMKII inhibitors that should also inhibit the putative direct Aβ binding. However, our study did not find any evidence for direct effects of Aβ on CaMKII: Aβ did not directly disrupt CaMKII holoenzymes, GluN2B binding, T286 autophosphorylation, or kinase activityin 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.Graphical abstractDisplay OmittedHighlights•Aβ and the CaMKII regulatory domain share a region of homology•Suppression of CaMKII movement in neurons by Aβ requires CaMKII activity•Aβ does not directly affect CaMKII activity, T286 phosphorylation, or GluN2B binding•Thus, the Aβ effects on CaMKII in neurons require indirect signaling mechanismsMolecular neuroscience; Cellular neuroscience
