Amyloid beta proteins inhibit Cl(-)-ATPase activity in cultured rat hippocampal neurons.

Abstract

Cl(-)-ATPase in the CNS is a candidate for an outwardly directed neuronal Cl(-) transporter requiring phosphatidylinositol-4-phosphate (PI4P) for its optimal activity. To test its pathophysiological changes in a phosphatidylinositol (PI) metabolism disorder, the effects of neurotoxic factors in Alzheimer's disease (AD), amyloid beta proteins (Abetas), on the Cl(-)-ATPase activity were examined using primary cultured rat hippocampal neurons. Amyloid beta proteins (1-40, 1-42 and 25-35) concentration-dependently (1-100 nM) and time-dependently (from 1 h to 6 day) decreased Cl(-)-ATPase activity and elevated intracellular Cl(-) concentrations ([Cl(-)]i), Abeta25-35 being the most potent. Addition of inositol or 8-Br-cyclic GMP completely reversed these Abeta-induced changes. The recoveries in enzyme activity were attenuated by an inhibitor of PI 4-kinase, 10 microM wortmannin or 20 microM quercetin, but not by a PI 3-kinase inhibitor, 50 nM wortmannin or 10 microM LY294002. The PI, PIP and PIP2 levels of the plasma membrane-rich fraction were lower in the Abeta-treated cells as compared with each control. In the Abeta-exposed culture, but not in control, stimulation by 10 microM glutamate for 10 min significantly increased fragmentation of DNA and decreased cell viability. Addition of inositol or 8-Br-cyclic GMP prevented the effect of Abeta-treatment on the neurotoxicity of glutamate. Thus, Abetas reduce neuronal Cl(-)-ATPase activity, resulting in an increase in [Cl(-)]i probably by lowering PI4P levels, and this may reflect a pre-apoptotic condition in early pathophysiological profiles of AD.

• Authors: K Yagyu, K Kitagawa, T Irie, B Wu, X T Zeng, N Hattori, C Inagaki
• Journal: Journal of neurochemistry (J Neurochem) Vol. 78 Issue 3 Pg. 569-76 (Aug 2001) ISSN: 0022-3042 [Print] England
• PMID: 11483660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Anion Transport Proteins
• Chlorides
• Enzyme Inhibitors
• Peptide Fragments
• Phosphatidylinositol Phosphates
• Phosphatidylinositols
• amyloid beta-protein (1-40)
• amyloid beta-protein (25-35)
• 8-Bromo Cyclic Adenosine Monophosphate
• Glutamic Acid
• Inositol
• Adenosine Triphosphatases
• anion-sensitive ATPases

Topics

• 8-Bromo Cyclic Adenosine Monophosphate (pharmacology)
• Adenosine Triphosphatases (antagonists & inhibitors, metabolism)
• Alzheimer Disease (physiopathology)
• Amyloid beta-Peptides (pharmacology)
• Animals
• Anion Transport Proteins
• Cell Fractionation
• Cell Survival (drug effects)
• Cells, Cultured
• Chlorides (metabolism)
• DNA Fragmentation (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Glutamic Acid (pharmacology)
• Hippocampus (cytology)
• Humans
• Inositol (pharmacology)
• Neurons (drug effects, enzymology)
• Peptide Fragments (pharmacology)
• Phosphatidylinositol Phosphates (metabolism)
• Phosphatidylinositols (metabolism)
• Rats
• Rats, Wistar
• Time Factors