title: Pitavastatin decreases tau levels via the inactivation of Rho/ROCK.
abstract: Epidemiological studies have shown that long-term treatment with statins decreases the risk of developing Alzheimer's disease. Statins have pleiotropic effects by lowering the concentration of isoprenoid intermediates. Although several studies have shown that statins may reduce amyloid beta protein levels, there have been few reports on the interaction between statins and tau. We report here that pitavastatin reduces total and phosphorylated tau levels in a cellular model of tauopathy, and in primary neuronal cultures. The decrease caused by pitavastatin is reversed by the addition of mevalonate, or geranylgeranyl pyrophosphate. The maturation of small G proteins, including RhoA was disrupted by pitavastatin, as was the activity of glycogen synthase kinase 3β (GSK3β), a major tau kinase. Toxin A, inhibitor of glycosylation of small G proteins, and Rho kinase (ROCK) inhibitor decreased phosphorylated tau levels. Rho kinase inhibitor also inactivated glycogen synthase kinase 3β. Although the mechanisms responsible for the reduction in tau protein by pitavastatin require further examination, this report sheds light on possible therapeutic approaches to tauopathy.
authors: Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. hamano@u-fukui.ac.jp
authors: Tadanori
authors: T
authors: Hamano
authors: Shu-Hui
authors: SH
authors: Yen
authors: Tania
authors: T
authors: Gendron
authors: Li-wen
authors: LW
authors: Ko
authors: Masaru
authors: M
authors: Kuriyama
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D004768:Enterotoxins / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D010766:Phosphorylation; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D004768:Enterotoxins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D011804:Quinolines; D016875:tau Proteins; C041348:tcdA protein, Clostridium difficile; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D054460:rho-Associated Kinases; D038362:Glycogen Synthase Kinase 3; D020559:Monomeric GTP-Binding Proteins; C108475:pitavastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid