The amyloid-beta-dependent phosphorylation of CRMP-2 and its contribution in Alzheimer’s disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Before the development of these two characteristic features, impairments in anterograde axonal transport develop. However, molecules that initiate these impairments are still unknown. The collapsin response mediator protein-2 (CRMP-2) plays an integral role in kinesin-1-dependent axonal transport and there is evidence that phosphorylation of CRMP-2 releases kinesin-1. However, the intraneuronal signaling events that regulate CRMP-2 phosphorylation and kinesin function during neurodegeneration are yet to be defined. Here, we tested the hypothesis that amyloid beta (Aβ)-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1 anterograde axonal motor transport protein in AD. We found enhanced Aβ-dependent phosphorylation of CRMP-2 at the T555 site and reduced CRMP-2 association with kinesin-1, while the overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon elongation. Additionally, in the transgenic Tg2576 mouse model of familial AD (FAD), that exhibits Aβ accumulation in the brain with age, we found substantial colocalization of pT555CRMP-2 and dystrophic neurites. Consistent with these findings, brain lysates from AD patients demonstrated phosphorylation of CRMP-2 at the T555 site correlated with the elevated dissociation of CRMP-2 from kinesin-1. These data suggest that Aβ-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport potential leading to neuronal defects.