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

A beta bears homology to the CaMKII regulatory domain, and peptides derived from this domain can bind and disrupt the CaMKII holoenzyme, suggesting that A beta could have a similar effect. Notably, A beta impairs the synaptic CaMKII accumulation that is mediated by GluN2B binding, which requires CaMKII assembly into holoenzymes. Furthermore, this A beta-induced impairment is prevented by CaMKII inhibitors that should also inhibit the putative direct A beta binding. However, our study did not find any evidence for direct effects of A beta on CaMKII: A beta did not directly disrupt CaMKII holoenzymes, GluN2B binding, T286 autophosphorylation, or kinase activity in vitro. Most importantly, in neurons, the A beta-induced impairment of CaMKII synaptic accumulation was prevented by an ATP-competitive CaMKII inhibitor that would not interfere with the putative direct A beta binding. Together, our results indicate that synaptic A beta effects are not mediated by direct binding to CaMKII, but instead require CaMKII activation via indirect signaling events.

Automated summary

A beta shares similarity with the CaMKII regulatory domain, but does not directly affect CaMKII function. The impairment of CaMKII induced by A beta at synapses is mediated by indirect signaling events.