The cdc2/cyclin B1 kinase is absent from neurons that are terminally differentiated. However, unscheduled activation of Cdc2/cyclin B and accumulation of mitotic phosphoepitopes have been described in degenerating neurons of Alzheimer's disease (AD), and their appearance precedes hallmark lesion formation. In cycling cells the timing of cdc2 activation and onset of mitosis are determined by the Wee1 tyrosine kinase. We therefore investigated the Wee1 kinase in human brain. Surprisingly, we have found that the enzyme is constitutively active in neurons of normal brain. Consistent with its behavior in M phase, Wee1 in AD has decreased activity, becomes MPM-2 immunoreactive, and is redistributed from its normally nuclear domain to the cytoplasm of affected neurons. These data suggest that Wee1 functions in normal postmitotic neurons, but is altered in AD so as to promote activation of Cdc2/cyclin B1. Thus, Wee1 is yet another mitotic regulator that participates in the AD neurodegenerative process.
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