Protective effects of estradiol against amyloid beta protein-induced inhibition of neuronal Cl(-)-ATPase activity.
Low concentrations of amyloid beta proteins (Abetas, 1-10 nM) were recently demonstrated to reduce Cl(-)-ATPase activity in parallel with an increase in the intracellular Cl(-) concentration ([Cl(-)]i) and decreases in plasma membrane phosphorylated phosphatidylinositol (PIP and PIP2) levels in cultured rat hippocampal neurons. In this study, 17 beta-estradiol (estradiol) at a therapeutic concentration (1.8 nM) for Alzheimer's disease was found to block these Abeta (Abeta25-35)-induced changes. This protective effect of estradiol on Cl(-)-ATPase activity was antagonized by a pure estrogen receptor antagonist, ICI182780 and inhibitors for cyclic GMP-dependent protein kinase (PKG) (KT5823), Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) (KN62) and phosphatidylinositol (PI) 4-kinase (wortmannin and quercetin). Estradiol recovered Abeta-induced decreases in plasma membrane phosphoinositide (PIP and PIP2) levels, this effect being inhibited by KT5823 and KN62. Glutamate toxicity was augmented in neurons with elevated [Cl(-)]i either by Abeta-treatment or carbachol+KCl+LiCl-treatment. The increased glutamate toxicity in the Abeta-treated neurons was attenuated by estradiol. Thus, a therapeutic concentration of estradiol protected Abeta-treated neurons against inhibition of Cl(-)-ATPase activity and an increase in [Cl(-)]i through its receptor, probably via PKG- and CaMKII(-)mediated recovery of PI4P formation. Elevated [Cl(-)]i may be related to enhancement of glutamate toxicity.
Yagyu
K
K
Department of Pharmacology, Kansai Medical University, 10-15 Fumizono-Cho Moriguchi City, 570-8506, Osaka, Japan.
Kitagawa
K
K
Wu
B
B
Zhang
N Y
NY
Irie
T
T
Hattori
N
N
Inagaki
C
C
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D027321:Anion Transport Proteins; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D027321:Anion Transport Proteins; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D004958:Estradiol; D000251:Adenosine Triphosphatases; C031652:anion-sensitive ATPases