Lithium reduces tau phosphorylation: effects in living cells and in neurons at therapeutic concentrations.
BACKGROUND
The mechanism of action of lithium remains to be determined satisfactorily. Recent studies suggested a possible role in inhibiting glycogen synthase kinase-3 (GSK-3), previously shown to phosphorylate the protein tau. Tau is expressed mainly in neurons, where it functions to stabilize microtubules in a phosphorylation-dependent manner.


METHODS
Neurons and transfected non-neuronal cells were treated with lithium and the phosphorylation of tau at multiple epitopes examined by western blotting and by immunocytochemistry. Using green fluorescent protein as a tag we examined the effects of lithium on phosphorylated tau in living cells.


RESULTS
Lithium reversibly reduced tau phosphorylation at therapeutic concentrations, and even at high concentrations did not alter neuronal morphology. Green fluorescent protein tagged-tau when phosphorylated by GSK-3 was diffusely distributed; treatment with lithium resulted in association with microtubules and then bundle formation. Removing lithium allowed observation of the dissolution of bundles and gradual dissociation of tau from microtubules in living cells.


CONCLUSIONS
Lithium may have multiple effects in brain, but at least one action is demonstrated to be a relative inhibition of GSK-3-induced tau phosphorylation. These results carry implications for future studies of the actions of mood-stabilizing drugs and indeed of the molecular mechanisms of affective disorders.
Lovestone
S
S
Department of Psychiatry, Institute of Psychiatry, London, United Kingdom.
Davis
D R
DR
Webster
M T
MT
Kaech
S
S
Brion
J P
JP
Matus
A
A
Anderton
B H
BH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D018692:Antimanic Agents / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D038341:Glycogen Synthase Kinases; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D008870:Microtubules / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D016875:tau Proteins / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D018692:Antimanic Agents; D016875:tau Proteins; D008094:Lithium; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases