Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo
Bibliographic
Year of Publication:
2005
Contact PI Name:
Karen Duff
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
National Institute of Neurological Disorders and Stroke (NINDS)
Alzheimer's Association
Study Goal and Principal Findings:
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.
Therapeutic Agent
Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Lithium
Therapeutic Target:
Multi Target
Animal Model
Model Information:
Species:
Mouse
Model Type:
Tau
Model Name:
JNPL3(P301L)
Strain/Genetic Background:
C57BL/DBA2/SW
Experimental Design
Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest
Outcomes
Outcome Measured
Outcome Parameters
Motor Function
Rotarod Test
Histopathology
Axonal Degeneration
Tau Pathology
Biochemical
Glycogen Synthase Kinase 3 alpha (GSK3 alpha)
Glycogen Synthase Kinase 3 beta (GSK3 beta)
phospho-Glycogen Synthase Kinase 3 beta (phospho-GSK3 beta)
Glycogen Synthase Kinase 3 beta (GSK3 beta) Activity
phospho-Protein Kinase B (phospho-Akt/PKB)
Brain-Heat Stable Soluble Tau
Sarkosyl Soluble Tau
Sarkosyl Insoluble Tau
Immunochemistry
Tau Protein
phospho-Tau
Microscopy
Vacuoles
Pharmacokinetics
Drug Concentration-Plasma
Toxicology
Body Weight