Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo.
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.
Noble
Wendy
W
Center for Dementia Research, Nathan S. Kline Institute, New York University, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
Planel
Emmanuel
E
Zehr
Cindy
C
Olm
Vicki
V
Meyerson
Jordana
J
Suleman
Farhana
F
Gaynor
Kate
K
Wang
Lili
L
LaFrancois
John
J
Feinstein
Boris
B
Burns
Mark
M
Krishnamurthy
Pavan
P
Wen
Yi
Y
Bhat
Ratan
R
Lewis
Jada
J
Dickson
Dennis
D
Duff
Karen
K
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
D004791:Enzyme Inhibitors; D000939:Epitopes; D016875:tau Proteins; D008094:Lithium; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride