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Collapsin response mediator protein‐2 hyperphosphorylation is an early event in Alzheimer’s disease progression
Author(s) -
Cole Adam R.,
Noble Wendy,
Aalten Lidy van,
Plattner Florian,
Meimaridou Rena,
Hogan Dale,
Taylor Margaret,
LaFrancois John,
GunnMoore Frank,
Verkhratsky Alex,
Oddo Salvatore,
LaFerla Frank,
Giese K. Peter,
Dineley Kelly T.,
Duff Karen,
Richardson Jill C.,
Yan Shi Du,
Hanger Diane P.,
Allan Stuart M.,
Sutherland Calum
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04829.x
Subject(s) - cyclin dependent kinase 5 , hyperphosphorylation , gsk 3 , phosphorylation , biology , tau protein , kinase , alzheimer's disease , presenilin , amyloid precursor protein , transgene , gsk3b , genetically modified mouse , microbiology and biotechnology , medicine , neuroscience , protein kinase a , cyclin dependent kinase 2 , biochemistry , disease , gene
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 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.