Pathophysiological concentrations of amyloid beta proteins directly inhibit rat brain and recombinant human type II
Bo Wu1, Kaori Kitagawa, Nan-Yan Zhang
1Department of Pharmacology, Kansai Medical University, Osaka, Japan.
Abstract:
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.
Insights
Amyloid beta proteins (Abetas) directly inhibit plasma membrane phosphatidylinositol 4-kinase II (PI4KII) activity at concentrations relevant to Alzheimer's disease. This reversible inhibition suggests PI4KII is a key target in disease pathogenesis.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Amyloid beta proteins (Abetas) are implicated in Alzheimer's disease pathogenesis.
- Previous studies indicated Abetas reduce phosphatidylinositol monophosphate levels and affect related enzyme activity in neurons.
Purpose of the Study:
- To investigate the in vitro effects of Abetas on phosphatidylinositol 4-kinase (PI4K) activity.
- To determine if plasma membrane PI4KII is a direct target of Abetas.
Main Methods:
- Enzyme activity assays using rat brain subcellular fractions and recombinant human PI4KII.
- Dose-response and kinetic analyses of Abeta inhibition on PI4KII, PI3K, and PI4KIII activities.
Main Results:
- Abeta25-35 inhibited PI4KII activity in plasma membrane-rich fractions and with recombinant PI4KIIalpha.
- Inhibition was dose-dependent, reversible, and non-competitive, occurring at pathophysiological Abeta concentrations.
- Neither PI3K nor PI4KIII activities were significantly inhibited by Abeta25-35 at the plasma membrane.
Conclusions:
- Pathophysiological concentrations of Abetas directly and reversibly inhibit plasma membrane PI4KII activity.
- Plasma membrane PI4KII is identified as a direct molecular target of Abetas.
- This finding provides a potential mechanism for Abeta's role in Alzheimer's disease pathogenesis.
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