Elevated neuronal Cdc2-like kinase activity in the Alzheimer disease brain

Neurofibrillary tangles (NFT) in Alzheimer's disease (AD) consist largely o f hyperphosphorylated tau protein. Many of the phosphorylation sites on tau are serine/threonine-proline sequences, several of which are phosphorylate d in vitro by neuronal Cdc2-like kinase (Nclk), a kinase composed of Cdk5 a nd its activator(s). Thus, tau hyperphosphorylation in AD may result in par t from deregulation of Ndlk. To test this hypothesis, we examined Nclk acti vity in prefrontal and cerebellar cortex from 15 postmortem AD and 16 age-m atched control subjects, and corrected either for Cdk5 level or for neurona l loss. The ratio of Nclk activity in prefrontal versus cerebellar cortex w as then compared. When corrections were made for neuronal loss, the ratios of kinase activity in prefrontal versus cerebellar cortex were significantl y higher in AD (6.45 +/- 0.86) than the controls (3.13 +/- 0.46; P = 0.003) . This finding is consistent with a role for Nclk in the pathogenesis of NF T in AD. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.