CASEIN KINASE-1 IS TIGHTLY ASSOCIATED WITH PAIRED-HELICAL FILAMENTS ISOLATED FROM ALZHEIMERS-DISEASE BRAIN

The protein kinase activity tightly associated with paired helical fil aments (PHFs) purified from the brain tissue of individuals with Alzhe imer's disease has been characterized in vitro. The activity is shown to phosphorylate casein, an exogenous substrate, with a maximal veloci ty of similar to 2 nmol/min/mg, suggesting it comprises a significant component of the total protein in the PHF preparation. On the basis of substrate selectivity, isoquinoline sulfonamide inhibitor selectivity , in-gel renaturation assays, and western analysis, the activity consi sts of closely related members of the alpha branch of the casein kinas e 1 family of protein kinases. Because of its tight association with P HFs and its phosphate-directed substrate selectivity, casein kinase 1 is positioned to participate in the pathological hyperphosphorylation of tau protein that is observed in neurodegenerative diseases such as Alzheimer's disease.