Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies.
Lithium, a widely used drug for treating affective disorders, is known to inhibit glycogen synthase kinase-3 (GSK-3), which is one of the major tau kinases. Thus, lithium could have therapeutic benefit in neurodegenerative tauopathies by reducing tau hyperphosphorylation. We tested this hypothesis and showed that long-term administration of lithium at relatively low therapeutic concentrations to transgenic mice that recapitulate Alzheimer's disease (AD)-like tau pathologies reduces tau lesions, primarily by promoting their ubiquitination rather than by inhibiting tau phosphorylation. These findings suggest novel mechanisms whereby lithium treatment could ameliorate tauopathies including AD. Because lithium also has been shown to reduce the burden of amyloid-beta pathologies, it is plausible that lithium could reduce the formation of both amyloid plaques and tau tangles, the two pathological hallmarks of AD, and thereby ameliorate the behavioral deficits in AD.
Nakashima
Hanae
H
Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, 700-8558, Okayama, Japan.
Ishihara
Takeshi
T
Suguimoto
Pilar
P
Yokota
Osamu
O
Oshima
Etsuko
E
Kugo
Aki
A
Terada
Seishi
S
Hamamura
Takashi
T
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
Kuroda
Shigetoshi
S
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008094:Lithium / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D010766:Phosphorylation; D024801:Tauopathies / Q000188:drug therapy*; D013997:Time Factors; D025801:Ubiquitin / Q000187:drug effects*; D016875:tau Proteins / Q000737:chemistry / Q000187:drug effects*
D025801:Ubiquitin; D016875:tau Proteins; D008094:Lithium; D038362:Glycogen Synthase Kinase 3