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Neural Regen Res. 2018 Jun;13(6):1066-1080. doi: 10.4103/1673-5374.233451.

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

Author information

1
Department of Neuroscience, Central Clinical School, Monash University, Prahran, Victoria, Australia.
2
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
3
Department of Anatomy & Developmental Biology, Monash University, Clayton, Victoria, Australia.
4
Department of Anatomical Pathology, Alfred Hospital, Prahran, Victoria, Australia.
5
Department of Anatomy & Developmental Biology, Monash University, Clayton; School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.
6
Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Ilisia, Athens, Greece.
7
The Henryk Niewodniczanski Institute of Nuclear Physics, Polish Academy of Sciences, Department of Applied Spectroscopy, Radzikowskiego, Krakow, Poland.
8
Centre for Biospectroscopy and Department of Microbiology, Monash University, Clayton, Victoria, Australia.

Abstract

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.

KEYWORDS:

amyloid-beta protein; collapsin response mediator protein; kinases; kinesin; microtubules; tubulin

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