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 normall y absent from terminally differentiated neurons of adult brain. However, un scheduled expression and activation of Cdc2/cyclin B has been seen in neuro ns undergoing degeneration in Alzheimer's disease. The presence of this mit otic kinase correlates with accumulation of mitotic phosphoepitopes in prot ein components of the hallmark neurofibrillary tangles. Of importance to th e 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 initia tes 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 i n mitotic cells, i.e. the Cdc25B tyrosine phosphatase, in Alzheimer's disea se brain. Although the enzyme appeared abundant in affected neurons, it was also evident in unaffected neurons of Alzheimer's disease and control brai n. Thus, we have found, surprisingly, that Cdc25B is a normal constituent o f adult brain neurons, with detectable basal levels of activity. In Alzheim er's disease the levels and activity of the enzyme are elevated, and the ac tive enzyme predominates in the cytoplasmic compartment of neurons. Consist ent with these M phase-type changes, Cdc25B displays increased immunoreacti vity towards the MPM-2 mitotic phosphoepitope antibody. We propose that aberrant expression of Cdc2/cyclin Bin Alzheimer's disease leads to potentiation of mitotic activation mediated by constitutive neuron al Cdc25B activity. As a result, various downstream indices of mitotic even ts are generated, eventually culminating in neurodegeneration. Our data als o 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 CM, a Cdc2-like kinase that is particularly enriched in brain. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.