Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression

Adam R. Cole, Wendy Noble, Lidy van Aalten, Florian Plattner, Rena Meimaridou, Dale Hogan, Margaret Taylor, John LaFrancois, Frank Gunn-Moore, Alex Verkhratsky, Salvatore Oddo, Frank LaFerla, K. Peter Giese, Kelly T. Dineley, Karen Duff, Jill C. Richardson, Shi Du Yan, Diane P. Hanger, Stuart M. Allan, Calum Sutherland

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    Abstract

    \ Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that can regulate microtubule assembly in neurons. This function of CRMP2 is regulated by phosphorylation by glycogen synthase kinase 3 (GSK3) and cyclin-dependent kinase 5 (Cdk5). Here, using novel phosphospecific antibodies, we demonstrate that phosphorylation of CRMP2 at Ser522 (Cdk5-mediated) is increased in Alzheimer's disease (AD) brain, while CRMP2 expression and phosphorylation of the closely related isoform CRMP4 are not altered. In addition, CRMP2 phosphorylation at the Cdk5 and GSK3 sites is increased in cortex and hippocampus of the triple transgenic mouse [presenilin-1 (PS1)(M146V)KI; Thy1.2-amyloid precursor protein (APP)(swe); Thy1.2tau(P301L)] that develops AD-like plaques and tangles, as well as the double (PS1(M146V)KI; Thy1.2-APP(swe)) transgenic mouse. The hyperphosphorylation is similar in magnitude to that in human AD and is evident by 2 months of age, ahead of plaque or tangle formation. Meanwhile, there is no change in CRMP2 phosphorylation in two other transgenic mouse lines that display elevated amyloid beta peptide levels (Tg2576 and APP/amyloid beta-binding alcohol dehydrogenase). Similarly, CRMP2 phosphorylation is normal in hippocampus and cortex of Tau(P301L) mice that develop tangles but not plaques. These observations implicate hyperphosphorylation of CRMP2 as an early event in the development of AD and suggest that it can be induced by a severe APP over-expression and/or processing defect.

    Original languageEnglish
    Pages (from-to)1132-1144
    Number of pages13
    JournalJournal of Neurochemistry
    Volume103
    Issue number3
    DOIs
    Publication statusPublished - Nov 2007

    Cite this

    Cole, A. R., Noble, W., van Aalten, L., Plattner, F., Meimaridou, R., Hogan, D., Taylor, M., LaFrancois, J., Gunn-Moore, F., Verkhratsky, A., Oddo, S., LaFerla, F., Giese, K. P., Dineley, K. T., Duff, K., Richardson, J. C., Yan, S. D., Hanger, D. P., Allan, S. M., & Sutherland, C. (2007). Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression. Journal of Neurochemistry, 103(3), 1132-1144. https://doi.org/10.1111/j.1471-4159.2007.04829.x