Abstract

Alzheimer's disease (AD) is characterised by the presence of extracellular amyloid plaques in the brain. They are composed of aggregated amyloid beta-peptide (A beta) misfolded into beta-sheets which are the cause of the AD memory impairment and dementia. Memory depends on the hippocampal formation and maintenance of synapses by long-term potentiation (LTP), whose main steps are the activation of NMDA receptors, the phosphorylation of CaMKII alpha and the nuclear translocation of the transcription factor CREB. It is known that A beta oligomers (oA beta) induce synaptic loss and impair the formation of new synapses. Here, we have studied the effects of oA beta on CaMKII alpha. We found that oA beta produce reactive oxygen species (ROS), that induce CaMKII alpha oxidation in human neuroblastoma cells as we assayed by western blot and immunofluorescence. Moreover, this oxidized isoform is significantly present in brain samples from AD patients. We found that the oxidized CaMKII alpha is active independently of the binding to calcium/calmodulin, and that CaMKII alpha phosphorylation is mutually exclusive with CaMKII alpha oxidation as revealed by immunoprecipitation and western blot. An in silico modelling of the enzyme was also performed to demonstrate that oxidation induces an activated state of CaMKII alpha. In brains from AD transgenic models of mice and in primary cultures of murine hippocampal neurons, we demonstrated that the oxidation of CaMKII alpha induces the phosphorylation of CREB and its translocation to the nucleus to promote the transcription of ARC and BDNF. Our data suggests that CaMKII alpha oxidation would be a pro-survival mechanism that is triggered when a noxious stimulus challenges neurons as do oA beta.