Regular ArticleImpaired Src signaling and post-synaptic actin polymerization in Alzheimer's disease mice hippocampus - Linking NMDA receptors and the reelin pathway

•Hippocampus of young 3xTg-AD male mice shows decreased GluN2B phosphorylation.•Modified GluN2B phosphorylation in 3xTg-AD mice correlates with Src activity.•The reelin pathway is modified in young 3xTg-AD male mice hippocampus and cortex.•Src activation in different 3xTg-AD's brain areas links to different pathways.•Actin polymerization is decreased in young 3xTg-AD male mice hippocampus.

Early cognitive deficits in Alzheimer's disease (AD) have been related to deregulation of N-methyl-d-aspartate receptors (NMDARs) and synaptic dysfunction in response to amyloid-beta peptide. NMDAR anchorage to post-synaptic membrane depends in part on Src kinase, which is also implicated in NMDAR activation and actin cytoskeleton stabilization, two processes relevant for normal synaptic function. In this study we analyzed the changes in GluN2B subunit phosphorylation and the levels of proteins involved in Src related signaling pathways linking the Tyr kinase to actin cytoskeleton polymerization, namely reelin, disabled-1 (Dab1) and cortactin, in hippocampal and cortical homogenates obtained from the triple transgenic mouse model of AD (3xTg-AD) that shows progression of pathology as a function of age versus age-matched wild-type mice. Moreover, we evaluated regional post-synaptic actin polymerization using phalloidin labeling in hippocampal slices. Young (3 month-old) 3xTg-AD male mice hippocampus exhibited decreased GluN2B Tyr1472 phosphorylation and reduced Src activity. In the cortex, decreased Src activity correlated with reduced levels of reelin and Dab1, implicating changes in the reelin pathway. We also observed diminished phosphorylated Dab1 and cortactin protein levels in the hippocampus and cortex of young 3xTg-AD male mice. Concordantly with the recognized role of these proteins in actin stabilization, we detected a significant decrease in post-synaptic F-actin in 3 month-old 3xTg-AD male CA1 and CA3 hippocampal regions. These data suggest deregulated Src-dependent signaling pathways involving GluN2B-composed NMDARs and post-synaptic actin cytoskeleton depolymerization in the hippocampus in early stages of AD.