Constitutive Cdc25B tyrosine phosphatase activity in adult brain neurons with M phase-type alterations in Alzheimer's disease.
The Cdc2/cyclin B kinase is a critical regulator of mitosis that is normally absent from terminally differentiated neurons of adult brain. However, unscheduled expression and activation of Cdc2/cyclin B has been seen in neurons undergoing degeneration in Alzheimer's disease. The presence of this mitotic kinase correlates with accumulation of mitotic phosphoepitopes in protein components of the hallmark neurofibrillary tangles. Of importance to the pathogenic mechanism of Alzheimer's disease is the striking appearance of Cdc2/cyclin B and mitotic phosphoepitopes prior to neurofibrillary tangle formation, which has suggested that a misappropriate mitotic cascade initiates and mediates the neurodegenerative process. To explain the atypical activation of Cdc2/cyclin B in degenerating neurons we have investigated the enzyme responsible for Cdc2/cyclin B activation in mitotic cells, i.e. the Cdc25B tyrosine phosphatase, in Alzheimer's disease brain. Although the enzyme appeared abundant in affected neurons, it was also evident in unaffected neurons of Alzheimer's disease and control brain. Thus, we have found, surprisingly, that Cdc25B is a normal constituent of adult brain neurons, with detectable basal levels of activity. In Alzheimer's disease the levels and activity of the enzyme are elevated, and the active enzyme predominates in the cytoplasmic compartment of neurons. Consistent with these M phase-type changes, Cdc25B displays increased immunoreactivity towards the MPM-2 mitotic phosphoepitope antibody. We propose that aberrant expression of Cdc2/cyclin B in Alzheimer's disease leads to potentiation of mitotic activation mediated by constitutive neuronal Cdc25B activity. As a result, various downstream indices of mitotic events are generated, eventually culminating in neurodegeneration. Our data also suggest that Cdc25B is functional in normal post-mitotic neurons lacking the mitotic Cdc2/cyclin B, but it does not appear to influence the activity of Cdk5, a Cdc2-like kinase that is particularly enriched in brain.
Vincent
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I
Department of Pathology, University of Washington, K056 HSB, P.O. Box 357705, Seattle, WA 98195, USA. ivincent@u.washington.edu
Bu
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Hudson
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Husseman
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Nochlin
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Jin
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D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D000911:Antibodies, Monoclonal / Q000276:immunology; D001921:Brain / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D017489:CDC28 Protein Kinase, S cerevisiae / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D008938:Mitosis / Q000235:genetics*; D008970:Molecular Weight; D016874:Neurofibrillary Tangles; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D020687:cdc25 Phosphatases / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D018797:Cell Cycle Proteins; D000939:Epitopes; D010446:Peptide Fragments; D051360:Cyclin-Dependent Kinase 5; D016203:CDC2 Protein Kinase; D017489:CDC28 Protein Kinase, S cerevisiae; C495905:CDK5 protein, human; D018844:Cyclin-Dependent Kinases; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases