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

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

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) M146VKI; Thy1.2-amyloid precursor protein (APP)swe; Thy1.2tauP301L] that develops AD-like plaques and tangles, as well as the double (PS1M146VKI; Thy1.2-APPswe) 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 β peptide levels (Tg2576 and APP/amyloid β-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 (US)
Pages (from-to)1132-1144
Number of pages13
JournalJournal of neurochemistry
Volume103
Issue number3
DOIs
StatePublished - Nov 2007

Keywords

  • Alzheimer's disease
  • Collapsin response mediator protein 2
  • Cyclin-dependent kinase 5
  • Glycogen synthase kinase 3
  • Phosphorylation

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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