Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease

R. Rademakers; K. Sleegers; J. Theuns; M. Van Den Broeck; S. Bel Kacem; L. G. Nilsson; R. Adolfsson; C. M. Van Duijn; C. Van Broeckhoven; M. Cruts

doi:10.1016/j.neurobiolaging.2004.10.003

Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease

R. Rademakers, K. Sleegers, J. Theuns, M. Van Den Broeck, S. Bel Kacem, L. G. Nilsson, R. Adolfsson, C. M. Van Duijn, C. Van Broeckhoven, M. Cruts

Neuroscience

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

23 Scopus citations

Abstract

Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.

Original language	English (US)
Pages (from-to)	1145-1151
Number of pages	7
Journal	Neurobiology of aging
Volume	26
Issue number	8
DOIs	https://doi.org/10.1016/j.neurobiolaging.2004.10.003
State	Published - Aug 2005

Keywords

Alzheimer dementia
Association analysis
Cyclin-dependent kinase
Mutation analysis
Neurodegeneration

ASJC Scopus subject areas

Clinical Neurology
Geriatrics and Gerontology
Aging
General Neuroscience
Developmental Biology

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10.1016/j.neurobiolaging.2004.10.003

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Rademakers, R., Sleegers, K., Theuns, J., Van Den Broeck, M., Bel Kacem, S., Nilsson, L. G., Adolfsson, R., Van Duijn, C. M., Van Broeckhoven, C., & Cruts, M. (2005). Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease. Neurobiology of aging, 26(8), 1145-1151. https://doi.org/10.1016/j.neurobiolaging.2004.10.003

Rademakers, R, Sleegers, K, Theuns, J, Van Den Broeck, M, Bel Kacem, S, Nilsson, LG, Adolfsson, R, Van Duijn, CM, Van Broeckhoven, C & Cruts, M 2005, 'Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease', Neurobiology of aging, vol. 26, no. 8, pp. 1145-1151. https://doi.org/10.1016/j.neurobiolaging.2004.10.003

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title = "Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease",

abstract = "Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.",

keywords = "Alzheimer dementia, Association analysis, Cyclin-dependent kinase, Mutation analysis, Neurodegeneration",

author = "R. Rademakers and K. Sleegers and J. Theuns and {Van Den Broeck}, M. and {Bel Kacem}, S. and Nilsson, {L. G.} and R. Adolfsson and {Van Duijn}, {C. M.} and {Van Broeckhoven}, C. and M. Cruts",

note = "Funding Information: We acknowledge the VIB Genetic Service Facility ( http://www.vibgeneticservicefacility.be/ ) for the genetic analyses. The research was funded by the Special Research Fund of the University of Antwerp, the Fund for Scientific Research Flanders (FWO-F), the Interuniversity Attraction Poles program P5/19 of the Belgian Federal Science Policy Office, the Medical Foundation Queen Elisabeth, and the International Alzheimer Research Foundation, Belgium; and The Netherlands Organization for Scientific Research (NWO), The Netherlands. R.R., J.T. and M.C. are postdoctoral fellows of the FWO-F. ",

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doi = "10.1016/j.neurobiolaging.2004.10.003",

language = "English (US)",

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AU - Rademakers, R.

AU - Sleegers, K.

AU - Theuns, J.

AU - Van Den Broeck, M.

AU - Bel Kacem, S.

AU - Nilsson, L. G.

AU - Adolfsson, R.

AU - Van Duijn, C. M.

AU - Van Broeckhoven, C.

AU - Cruts, M.

N1 - Funding Information: We acknowledge the VIB Genetic Service Facility ( http://www.vibgeneticservicefacility.be/ ) for the genetic analyses. The research was funded by the Special Research Fund of the University of Antwerp, the Fund for Scientific Research Flanders (FWO-F), the Interuniversity Attraction Poles program P5/19 of the Belgian Federal Science Policy Office, the Medical Foundation Queen Elisabeth, and the International Alzheimer Research Foundation, Belgium; and The Netherlands Organization for Scientific Research (NWO), The Netherlands. R.R., J.T. and M.C. are postdoctoral fellows of the FWO-F.

PY - 2005/8

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N2 - Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.

AB - Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.

KW - Alzheimer dementia

KW - Association analysis

KW - Cyclin-dependent kinase

KW - Mutation analysis

KW - Neurodegeneration

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ER -

Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease

Abstract

Keywords

ASJC Scopus subject areas

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