ABNORMAL ALZHEIMER-LIKE PHOSPHORYLATION OF TAU-PROTEIN BY CYCLIN-DEPENDENT KINASES CDK2 AND CDK5

We have shown earlier that certain proline-directed kinases such as MA P kinase or GSK-3 can phosphorylate tau protein in an abnormal manner reminiscent of tau from Alzheimer paired helical filaments [Drewes et al. (1992); Mandelkow et al. (1992)]. Both kinases are abundant in bra in tissue and associate physically with microtubules through several c ycles of assembly and disassembly. In this report we show that cdk2/cy clinA incorporates approximate to 5 P-i into recombinant tau, and that it also induces the M(R) shift and antibody reactivity typical of Alz heimer tau. However, since there is no cdk2 in brain [Meyerson et al. (1992)] we looked for other members of this family of kinases. Using a n antibody against the conserved N-terminus we isolated a cdk-like kin ase from brain which was capable of inducing the Alzheimer-like charac teristics in tan by phosphorylation. Its size (31 kDa), target specifi city (proline-directed), chromatographic behavior, and abundance in br ain suggest that this kinase is similar or identical to the neuronal c dc2-like kinase nclk alias PSSARLE or cdk5 [Hellmich et al. (1992); Me yerson et al. (1992); Xiong et al. (1992); Tsai et al. (1993)]. This w as confirmed by an antibody specific for cdk5. Like MAP kinase and GSK -3, this kinase is physically associated with microtubules and can be enriched by cycles of microtubule assembly and disassembly. Thus, cdk5 should be regarded as another kinase that could be held responsible f or the changes in tau protein during Alzheimer disease progression.