Amyloid beta-protein stimulates casein kinase I and casein kinase II activities.
Amyloid beta-protein (A beta) 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 A beta with the amino-acid sequence corresponding to cerebrovascular A beta and plaque A beta 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. A beta was found to stimulate markedly CK I- and CK II-mediated phosphorylation of casein in a concentration-dependent manner. The effect of plaque A beta was considerably higher than that of cerebrovascular A beta. Heparin, which is known to be a specific inhibitor of CK II, completely inhibited A beta-stimulated CK II activity. A beta 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 A beta 1-40 or blocked A beta. We propose that A beta, 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 A beta with protein kinases, thus, may characterize the beginning of the disease.
Chauhan
A
A
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314-6399.
Chauhan
V P
VP
Murakami
N
N
Brockerhoff
H
H
Wisniewski
H M
HM
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000201:enzymology; D047390:Casein Kinase II; D047388:Casein Kinases; D002417:Cattle; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D013379:Substrate Specificity
D016229:Amyloid beta-Peptides; D007527:Isoenzymes; D009842:Oligopeptides; D011494:Protein Kinases; D047390:Casein Kinase II; D047388:Casein Kinases; D017346:Protein Serine-Threonine Kinases