Modulation of the JNK and p38 pathways by cdk5 protein kinase in a transgenic mouse model of Alzheimer's disease.
In this study we have used the transgenic mouse model Tg2576 to analyze the involvement of anomalous loss of regulation of cdk5 and the stress kinases JNK and p38 in brain neuronal death as related to neurodegenerative disorders such as Alzheimer's disease. Previous studies on hippocampal cells led us to the discovery that the cdk5/p35 complex is activated in neurodegeneration, a finding that was confirmed later in the transgenic mouse model. Here we show a link between the cdk5 system and JNK and p38 phosphoproteins, as an alternative pathway to neuronal death. Brains of the Tg2576 transgenic mice overexpressing amyloid precursor protein exhibited immunoreactivity with the phosphoproteins p-JNK, p-p38 and the GTPase protein Rac1 surrounding neuritic plaques. A significant increase in the immunodetection of JNK and p38 phosphoproteins in the Tg2576 mouse compared with wild type controls confirmed these findings. The significant increase in co-immunoprecipitation of p-JNK, p-p38 and Rac1 proteins with cdk5 in the transgenic mouse provided evidence for these interactions. At the cellular level, p-JNK and cdk5 colocalized in the cytoplasm of the cell bodies and neurites of brain cortical areas of the transgenic mouse. The present evidence suggests a cellular link between the cdk5 system and the stress kinase JNK and p38 pathways in an in vivo model. This study sheds new light on the pathogenesis of neuronal degeneration processes such as those occurring in Alzheimer's disease.
Otth
Carola
C
Laboratory of Cellular and Molecular Biology, Millennium Institute for Advanced Studies in Cell Biology and Biotechnology (CBB), Faculty of Sciences, Universidad de Chile, Edificio Milenio, Las Encinas 3370, Nuñoa, Santiago, Chile.
Mendoza-Naranjo
Ariadna
A
Mujica
Lorena
L
Zambrano
Angara
A
Concha
Ilona I
II
Maccioni
Ricardo B
RB
D000544:Alzheimer Disease / Q000201:enzymology*; D000818:Animals; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000032:analysis / Q000378:metabolism*; D004195:Disease Models, Animal; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000032:analysis / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases