CRMP2 Hyperphosphorylation is Characteristic of Alzheimer's Disease and not a Feature Common to Other Neurodegenerative Diseases

Ritchie Williamson, Lidy van Aalten, David M. A. Mann, Bettina Platt, Florian Plattner, Lynn Bedford, John Mayer, David Howlett, Alessia Usardi, Calum Sutherland, Adam R. Cole

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    43 Citations (Scopus)

    Abstract

    Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that regulates neurite outgrowth. It is phosphorylated by Cdk5 and GSK3, and these modifications are abnormally high in the brains of Alzheimer's disease (AD) patients. Increased phosphorylation of CRMP2 is also apparent in mouse models of AD that express mutated A beta PP and PSEN1, but not A beta PP or tau alone, where it is detectable before the appearance of amyloid plaques and neurofibrillary tangles, suggesting it is an early event in AD pathogenesis. Here, we have extended these observations by showing that CRMP2 is not hyperphosphorylated in mice overexpressing mutated PSEN1 alone, or in cultured neurons treated with soluble, oligomeric A beta(42) peptide. Similarly, CRMP2 phosphorylation was not increased in a mouse model of severe neurodegeneration (PMSC-1 knockout) or in cultured neurons subjected to neurotoxic concentrations of NMDA or staurosporine. Most interestingly, CRMP2 phosphorylation was not increased in frontal cortex from patients with frontotemporal lobar degeneration associated with mutations in MAPT or with Pick bodies. Together, these observations are consistent with the hypothesis that abnormal phosphorylation of CRMP2 is specific to AD and occurs downstream of excessive processing of A beta PP, but that neither excessive A beta(42) peptide nor neurotoxicity alone are sufficient to promote hyperphosphorylation.

    Original languageEnglish
    Pages (from-to)615-625
    Number of pages11
    JournalJournal of Alzheimer's Disease
    Volume27
    Issue number3
    DOIs
    Publication statusPublished - 2011

    Keywords

    • Alzheimer's disease
    • Cdk5
    • CRMP2
    • GSK3
    • neurodegeneration
    • phosphorylation
    • RESPONSE MEDIATOR PROTEIN-2
    • GROWTH-CONE COLLAPSE
    • A-BETA
    • TRANSGENIC MICE
    • NEUROFIBRILLARY TANGLES
    • HIPPOCAMPAL-NEURONS
    • MUTANT PRESENILIN-1
    • PHOSPHORYLATION
    • TAUOPATHIES
    • DEPOSITION

    Cite this

    Williamson, R., van Aalten, L., Mann, D. M. A., Platt, B., Plattner, F., Bedford, L., Mayer, J., Howlett, D., Usardi, A., Sutherland, C., & Cole, A. R. (2011). CRMP2 Hyperphosphorylation is Characteristic of Alzheimer's Disease and not a Feature Common to Other Neurodegenerative Diseases. Journal of Alzheimer's Disease, 27(3), 615-625. https://doi.org/10.3233/JAD-2011-110617