Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse.

Abstract

Iron accumulation and tau protein deposition are pathological features of Alzheimer's (AD) and Parkinson's diseases (PD). Soluble tau protein is lower in affected regions of these diseases, and we previously reported that tau knockout mice display motor and cognitive behavioral abnormities, brain atrophy, neuronal death in substantia nigra, and iron accumulation in the brain that all emerged between 6 and 12 months of age. This argues for a loss of tau function in AD and PD. We also showed that treatment with the moderate iron chelator, clioquinol (CQ) restored iron levels and prevented neuronal atrophy and attendant behavioral decline in 12-month old tau KO mice when commenced prior to the onset of deterioration (6 months). However, therapies for AD and PD will need to treat the disease once it is already manifest. So, in the current study, we tested whether CQ could also rescue the phenotype of mice with a developed phenotype. We found that 5-month treatment of symptomatic (13 months old) tau KO mice with CQ increased nigral tyrosine hydroxylase phosphorylation (which induces activity) and reversed the motor deficits. Treatment also reversed cognitive deficits and raised BDNF levels in the hippocampus, which was accompanied by attenuated brain atrophy, and reduced iron content in the brain. These data raise the possibility that lowering brain iron levels in symptomatic patients could reverse neuronal atrophy and improve brain function, possibly by elevating neurotrophins.

• Authors: Peng Lei, Scott Ayton, Ambili Thoppuvalappil Appukuttan, Irene Volitakis, Paul A Adlard, David I Finkelstein, Ashley I Bush
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 81 Pg. 168-75 (Sep 2015) ISSN: 1095-953X [Electronic] United States
• PMID: 25796563 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Metals
• tau Proteins
• 3,4-Dihydroxyphenylacetic Acid
• Clioquinol
• Tyrosine 3-Monooxygenase
• Dopamine

Topics

• 3,4-Dihydroxyphenylacetic Acid (metabolism)
• Animals
• Brain (drug effects, pathology)
• Clioquinol (therapeutic use)
• Dementia (drug therapy, genetics, pathology)
• Disease Models, Animal
• Dopamine (metabolism)
• Maze Learning (drug effects)
• Metals (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Motor Activity (drug effects, genetics)
• Muscle Strength (drug effects, genetics)
• Neurons (drug effects, metabolism)
• Parkinsonian Disorders (drug therapy, genetics, pathology)
• Rotarod Performance Test
• Substantia Nigra (pathology)
• Tyrosine 3-Monooxygenase (metabolism)
• tau Proteins (deficiency, genetics)