Biomaterial Database

Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer's disease. 2018

Sara H Mokhtar, and Min Joung Kim, and Kylie A Magee, and Pei Mun Aui, and Speros Thomas, and Maha M Bakhuraysah, and Amani A Alrehaili, and Jae Young Lee, and David L Steer, and Rachel Kenny, and Catriona McLean, and Michael F Azari, and Antonis Birpanagos, and Ewlina Lipiec, and Philip Heraud, and Bayden Wood, and Steven Petratos

Department of Neuroscience, Central Clinical School, Monash University, Prahran, Victoria, Australia.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles. Prior to the development of these characteristic pathological hallmarks of AD, anterograde axonal transport is impaired. However, the key proteins that initiate these intracellular impairments remain elusive. 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. Here, we tested the hypothesis that amyloid-beta (Aβ)-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1 (an anterograde axonal motor transport protein) in AD. We found that brain sections and lysates from AD patients demonstrated elevated phosphorylation of CRMP-2 at the T555 site. Additionally, in the transgenic Tg2576 mouse model of familial AD (FAD) that exhibits Aβ accumulation in the brain with age, we found substantial co-localization of pT555CRMP-2 and dystrophic neurites. In SH-SY5Y differentiated neuronal cultures, Aβ-dependent phosphorylation of CRMP-2 at the T555 site was also elevated and this reduced the CRMP-2 association with kinesin-1. The overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon elongation. These data suggest that Aβ-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport protein function, leading to neuronal defects.