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We have shown previously that M-phase phospho-epitopes accumulate in neuronal tau proteins incorporated into the hallmark neurofibrillary tangles (NFT) of Alzheimer’s disease (AD). In M phase, the epitopes are produced by cdc2/cyclin B1 kinase by a highly conserved mechanism believed to be quiescent in terminally differentiated neurons of adult brain. To determine whether an M-phase mechanism is possible in AD neurons, we first investigated the presence of cdc2 and cyclin B1 in AD. Both proteins were enriched in neurons with NFT and in neurons susceptible to NFT. An antibody specific for catalytically active cdc2 stained numerous NFT-containing neurons in AD but did not react with normal neurons. Double-labeling studies showed that active cdc2 and cyclin B1 coexist in AD neurons and co-localize with AD-specific mitotic phospho-epitopes. Mitotic kinase purified from AD and normal brain, using the yeast p13suc1 protein as affinity ligand, showed higher histone H1 phosphorylation activity in AD. Accordingly, the levels of cdc2 and cyclin B1 in p13suc1 fractions from AD were higher than normal. Consistent with a physiological relationship between NFT and mitotic kinase, NFT proteins co-purified with and became phosphorylated by the p13suc1-bound kinase in vitro. Furthermore, cdc2/cyclin B1 is the only one of several proline-directed kinases that created the TG/MC mitotic phospho-epitopes in recombinant tau in vitro. These findings suggest that aberrantly reexpressed cdc2/cyclin B1 in NFT-bearing neurons in AD brain contributes to the generation of M-phase phospho-epitopes in NFT.

Aberrant Expression of Mitotic Cdc2/Cyclin B1 Kinase in Degenerating Neurons of Alzheimer’s Disease Brain