AMYLOID BETA-PROTEIN STIMULATES CASEIN KINASE-I AND CASEIN KINASE-II ACTIVITIES

Amyloid beta-protein (Abeta) is the major protein of cerebrovascular and plaque amyloid in Alzheimer's disease (AD). Extensive evidence has demonstrated abnormal protein phosphorylation in this disease. We investigated the effect of synthetic Abeta with the amino-acid sequence corresponding to cerebrovascular Abeta and plaque Abeta on the activities of casein kinase I (CK I) and casein kinase II (CK II). These enzymes were purified from bovine brain and casein was used as a substrate. Abeta was found to stimulate markedly CK I- and CK II-mediated phosphorylation of casein in a concentration-dependent manner. The effect of plaque Abeta was considerably higher than that of cerebrovascular Abeta. Heparin, which is known to be a specific inhibitor of CK II, completely inhibited Abeta-stimulated CK II activity. Abeta itself was not a substrate for casein kinases. These findings were confirmed using other substrates for CK I and CK II. The experiments with synthetic CK II-substrate peptide (Leu-Glu-Leu-Ser-Asp-Asp-Asp-Asp-Glu) and the phosphorylation of erythrocyte membrane proteins by intrinsic membrane-bound CK I in erythrocytes showed marked stimulation in activities of casein kinases in the presence of Abeta 1-40 or blocked Abeta. We propose that Abeta, by stimulating casein kinases, may contribute to abnormal protein phosphorylation in AD, in particular to increased phosphorylation of microtubule-associated proteins, leading to the neurofibrillary tangles formation and neurodegeneration in this disease. Interaction of Abeta with protein kinases, thus, may characterize the beginning of the disease.