Effects of Alzheimer's disease-related beta amyloid protein fragments on enzymes metabolizing phosphoinositides in brain.
Phosphatidylinositol 4-kinase (PI 4-kinase) and phosphatidylinositol 4-phosphate kinase (PIP kinase) were assayed in membranes prepared from samples of human frontal cortex initially frozen at autopsy. PI 4-kinase activity was significantly lower in Alzheimer's disease patients relative to age-matched controls or patients with Parkinson's disease. PIP kinase was not different in Alzheimer's versus age-matched controls. The beta amyloid protein fragment 1-40 inhibited PI 4-kinase activity in assays of control human or rat cortical membranes. Fragments 1-28 and 25-35 could not mimic the effects of fragment 1-40 while a reverse peptide 40-1 was equipotent. The inhibition of PI 4-kinase by fragment 1-40 was competitive with substrate. The beta amyloid protein fragments had diverse effects on phosphoinositide-specific phospholipase C (PI-PLC) as assayed in rat cortical membranes. Low concentrations of fragment 1-40 stimulated, while high concentrations of 1-40 or 40-1 inhibited PI-PLC activity. Fragment 25-35 stimulated PI-PLC nearly 3-fold, while fragment 1-28 had only minor effects on the enzyme. The results suggest alterations in phosphoinositide metabolism in Alzheimer's disease which could affect signal transduction and/or cytoskeletal organization.
Wallace
M A
MA
Department of Biochemistry, University of Tennessee, Memphis 38163.
D019870:1-Phosphatidylinositol 4-Kinase; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001344:Autopsy; D001921:Brain / Q000201:enzymology*; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D019269:Phosphatidylinositol 4,5-Diphosphate; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D054801:Phosphoinositide Phospholipase C; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D017853:Phosphotransferases (Alcohol Group Acceptor); D019870:1-Phosphatidylinositol 4-Kinase; C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D010727:Phosphoric Diester Hydrolases; D054801:Phosphoinositide Phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase