Amyloid β-protein stimulates casein kinase I and casein kinase II activities

Abstract

Amyloid β-protein (Aβ) 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 Aβ with the amino-acid sequence corresponding to cerebrovascular Aβ and plaque Aβ 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. Aβ was found to stimulate markedly CK I- and CK II-mediated phosphorylation of casein in a concentration-dependent manner. The effect of plaque Aβ was considerably higher than that of cerebrovascular Aβ. Heparin, which is known to be a specific inhibitor of CK II, completely inhibited Aβ-stimulated CK II activity. Aβ 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 Aβ 1–40 or blocked Aβ. We propose that Aβ, 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 Aβ with protein kinases, thus, may characterize the beginning of the disease.