Pitavastatin decreases tau levels via the inactivation of Rho/ROCK

• Published in: Neurobiology of aging Vol. 33; no. 10; pp. 2306 - 2320
• Main Authors: Hamano, Tadanori, Yen, Shu-Hui, Gendron, Tania, Ko, Li-wen, Kuriyama, Masaru
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2012
• Subjects: Aging; Alzheimer's disease; Animals; Bacterial Toxins - pharmacology; beta -Amyloid; Cell culture; Cells, Cultured; Enterotoxins - pharmacology; Female; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Glycogen synthase kinase 3β; Glycosylation; Guanine nucleotide-binding protein; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Internal Medicine; Male; mevalonic acid; Mevalonic Acid - pharmacology; Mice; Monomeric GTP-Binding Proteins - metabolism; Nervous system; Neurodegenerative diseases; Neurology; Neuronal cellular model; Neurons - drug effects; Phosphorylation; Pleiotrophic effects; Polyisoprenyl Phosphates - pharmacology; pyrophosphates; Quinolines - pharmacology; Rho-associated kinase; rho-Associated Kinases - antagonists & inhibitors; Rho/ROCK; RhoA protein; Small G protein; Statin; statins; Tau; Tau protein; tau Proteins - metabolism; Terpenes; Toxin A; Neuronal cellular model; Rho/ROCK; Glycogen synthase kinase 3β; Tau; Small G protein; Statin; Pleiotrophic effects
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2011.10.020

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.