Hyperphosphorylation of RNA polymerase II and reduced neuronal RNA levels precede neurofibrillary tangles in Alzheimer disease

Affected neurons of Alzheimer disease (AD) brain are distinguished by the p resence of the cell cycle cdc2 kinase and mitotic phosphoepitopes. A signif icant body of previous data has documented a decrease in neuronal RNA level s and nucleolar volume in AD brain. Here we present evidence that integrate s these seemingly distinct findings and offers an explanation for the degen erative outcome of the disease. During mitosis cdc2 phosphorylates and inhi bits the major transcriptional regulator RNA polymerase II (RNAP II). We th erefore investigated cdc2 phosphorylation of RNAP IT in AD brain. Using the H5 and H14 monoclonal antibodies specific for the cdc2-phosphorylated site s in RNAP II, we found that the polymerase is highly phosphorylated in AD. Moreover, RNAP II in AD translocates from its normally nuclear compartment to the cytoplasm of affected neurons, where it colocalizes with cdc2. These M phase-like changes in RNAP II correlate with decreased levels of poly-A RNA in affected neurons. Significantly, they precede tau phosphorylation an d neurofibrillary tangle formation. Our data support the hypothesis that in appropriate activation of the cell cycle cdc2 kinase in differentiated neur ons contributes to neuronal dysfunction and degeneration in part by inhibit ing RNAP II and cellular processes dependent on transcription.