Pathophysiological concentrations of amyloid beta proteins directly inhibit rat brain and recombinant human type II phosphatidylinositol 4-kinase activity.
We previously found that pathophysiological concentrations (< or = 10 nm) of an amyloid beta protein (Abeta25-35) reduced the plasma membrane phosphatidylinositol monophosphate level in cultured rat hippocampal neurons with a decrease in phosphatidylinositol 4-monophosphate-dependent Cl- -ATPase activity. As this suggested an inhibitory effect of Abeta25-35 on plasma membrane phosphatidylinositol 4-kinase (PI4K) activity, in vitro effects of Abetas on PI4K activity was examined using rat brain subcellular fractions and recombinant human type II PI4K (PI4KII). Abeta25-35 (10 nm) inhibited PI4KII activity, but neither PI 3-kinase (PI3K) nor type III PI4K (PI4KIII) activity, in microsomal fractions, while 100 nm Abeta25-35 inhibited PI3K activity in mitochondrial fractions. In plasma membrane-rich fractions, Abetas (> 0.5 nm) dose-dependently inhibited PI4KII activity, the maximal inhibition to 77-87% of control being reached around 10 nm of Abetas without significant changes in apparent Km values for ATP and PI, suggesting non-competitive inhibition by Abetas. The inhibition by 10 nm Abeta25-35 was reversible. In recombinant human PI4KIIalpha, inhibition profiles of Abetas were similar to those in rat brain plasma membranes. Therefore, pathophysiological concentrations of Abetas directly and reversibly inhibited plasma membrane PI4KII activity, suggesting that plasma membrane PI4KII is a target of Abetas in the pathogenesis of Alzheimer's disease.
Wu
Bo
B
Department of Pharmacology, Kansai Medical University, Osaka, Japan.
Kitagawa
Kaori
K
Zhang
Nan-Yan
NY
Liu
Bing
B
Inagaki
Chiyoko
C
D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D016296:Mutagenesis / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013347:Subcellular Fractions / Q000187:drug effects; D000077191:Wortmannin
D016229:Amyloid beta-Peptides; D000730:Androstadienes; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011994:Recombinant Proteins; C074636:amyloid beta-protein (25-35); D000255:Adenosine Triphosphate; D019870:1-Phosphatidylinositol 4-Kinase; D000241:Adenosine; D000077191:Wortmannin