Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons.
In Alzheimer's disease, tau protein becomes hyperphosporylated, which can contribute to neuronal degeneration. However, the implicated protein kinases are still unknown. Now we report that lithium (an inhibitor of glycogen synthase kinase-3) causes tau dephosphorylation at the sites recognized by antibodies Tau-1 and PHF-1 both in cultured neurons and in vivo in rat brain. This is consistent with a major role for glycogen synthase kinase-3 in modifying proline-directed sites on tau protein within living neurons under physiological conditions. Lithium also blocks the Alzheimer's disease-like proline-directed hyperphosphorylation of tau protein which is observed in neurons treated with a phosphatase inhibitor. These data raise the possibility of using lithium to prevent tau hyperphosphorylation in Alzheimer's disease.
Muñoz-Montaño
J R
JR
Centro de Biología Molecular Severo Ochoa, Facultad de Ciencias, Universidad Autónoma de Madrid, Spain.
Moreno
F J
FJ
Avila
J
J
Diaz-Nido
J
J
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D007701:Kinetin; D008094:Lithium / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011392:Proline / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D051381:Rats; D016875:tau Proteins / Q000276:immunology / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D011687:Purines; D016875:tau Proteins; D019319:Okadaic Acid; C090046:olomoucine; D011392:Proline; D008094:Lithium; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; D007701:Kinetin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one