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

doi:10.1111/j.1471-4159.2007.04829.x

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

Psychiatry

Research output: Contribution to journal › Article › peer-review

145 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; Thy1.2tau_P301L] that develops AD-like plaques and tangles, as well as the double (PS1_M146VKI; 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.

Original language	English (US)
Pages (from-to)	1132-1144
Number of pages	13
Journal	Journal of Neurochemistry
Volume	103
Issue number	3
DOIs	https://doi.org/10.1111/j.1471-4159.2007.04829.x
State	Published - 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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10.1111/j.1471-4159.2007.04829.x

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Cole, A. R., Noble, W., Aalten, L. V., 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

Cole, AR, Noble, W, Aalten, LV, Plattner, F, Meimaridou, R, Hogan, D, Taylor, M, LaFrancois, J, Gunn-Moore, F, Verkhratsky, A, Oddo, S, Laferla, F, Giese, KP, Dineley, KT, Duff, K, Richardson, JC, Yan, SD, Hanger, DP, Allan, SM & Sutherland, C 2007, 'Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression', Journal of Neurochemistry, vol. 103, no. 3, pp. 1132-1144. https://doi.org/10.1111/j.1471-4159.2007.04829.x

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

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.",

keywords = "Alzheimer's disease, Collapsin response mediator protein 2, Cyclin-dependent kinase 5, Glycogen synthase kinase 3, Phosphorylation",

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

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AU - Cole, Adam R.

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AU - Plattner, Florian

AU - Meimaridou, Rena

AU - Hogan, Dale

AU - Taylor, Margaret

AU - LaFrancois, John

AU - Gunn-Moore, Frank

AU - Verkhratsky, Alex

AU - Oddo, Salvatore

AU - Laferla, Frank

AU - Giese, K. Peter

AU - Dineley, Kelly T.

AU - Duff, Karen

AU - Richardson, Jill C.

AU - Yan, Shi Du

AU - Hanger, Diane P.

AU - Allan, Stuart M.

AU - Sutherland, Calum

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N2 - 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.

AB - 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.

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

Abstract

Keywords

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