title: Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo.
abstract: Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo, transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride-treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are involved in tauopathy progression and that kinase inhibitors may be effective therapeutically.
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, New York University, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Noble
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
authors.forename: Cindy
authors.initials: C
authors.lastname: Zehr
authors.forename: Vicki
authors.initials: V
authors.lastname: Olm
authors.forename: Jordana
authors.initials: J
authors.lastname: Meyerson
authors.forename: Farhana
authors.initials: F
authors.lastname: Suleman
authors.forename: Kate
authors.initials: K
authors.lastname: Gaynor
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: LaFrancois
authors.forename: Boris
authors.initials: B
authors.lastname: Feinstein
authors.forename: Mark
authors.initials: M
authors.lastname: Burns
authors.forename: Pavan
authors.initials: P
authors.lastname: Krishnamurthy
authors.forename: Yi
authors.initials: Y
authors.lastname: Wen
authors.forename: Ratan
authors.initials: R
authors.lastname: Bhat
authors.forename: Jada
authors.initials: J
authors.lastname: Lewis
authors.forename: Dennis
authors.initials: D
authors.lastname: Dickson
authors.forename: Karen
authors.initials: K
authors.lastname: Duff
mesh_terms: D000818:Animals; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000939:Epitopes; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008094:Lithium / Q000737:chemistry; D018021:Lithium Chloride / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010766:Phosphorylation; D024801:Tauopathies; D016875:tau Proteins / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D000939:Epitopes; D016875:tau Proteins; D008094:Lithium; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride