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Pathophysiological concentrations of amyloid β proteins directly inhibit rat brain and recombinant human type II phosphatidylinositol 4‐kinase activity
Author(s) -
Wu Bo,
Kitagawa Kaori,
Zhang NanYan,
Liu Bing,
Inagaki Chiyoko
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02805.x
Subject(s) - phosphatidylinositol , biochemistry , kinase , recombinant dna , biology , in vitro , cytosol , microsome , chemistry , microbiology and biotechnology , biophysics , enzyme , gene
We previously found that pathophysiological concentrations (≤ 10 n m ) of an amyloid β protein (Aβ25–35) 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 Aβ25–35 on plasma membrane phosphatidylinositol 4‐kinase (PI4K) activity, in vitro effects of Aβs on PI4K activity was examined using rat brain subcellular fractions and recombinant human type II PI4K (PI4KII). Aβ25–35 (10 n m ) inhibited PI4KII activity, but neither PI 3‐kinase (PI3K) nor type III PI4K (PI4KIII) activity, in microsomal fractions, while 100 n m Aβ25–35 inhibited PI3K activity in mitochondrial fractions. In plasma membrane‐rich fractions, Aβs (> 0.5 n m ) dose‐dependently inhibited PI4KII activity, the maximal inhibition to 77–87% of control being reached around 10 n m of Aβs without significant changes in apparent K m values for ATP and PI, suggesting non‐competitive inhibition by Aβs. The inhibition by 10 n m Aβ25–35 was reversible. In recombinant human PI4KIIα, inhibition profiles of Aβs were similar to those in rat brain plasma membranes. Therefore, pathophysiological concentrations of Aβs directly and reversibly inhibited plasma membrane PI4KII activity, suggesting that plasma membrane PI4KII is a target of Aβs in the pathogenesis of Alzheimer's disease.