Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degenerationin vivo

Abstract

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.phosphorylation ͉ neurofibrillary tangles ͉ Alzheimer's disease ͉ tau protein

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…131,132 Lithium, a well-characterized mood-stabilizer, competes with magnesium for GSK-3 binding; it leads to reduced tau-phosphorylation, aggregation and axonal degeneration in transgenic mice. 133,134 Valproate, another mood-stabilizing drug (and an antiepileptic), also inhibits GSK-3␤ and is currently being tested in clinical AD trials.…”

Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease

“…9 Interestingly, the inhibition of GSK-3b has been shown to protect against Ab neurotoxicity in mice models of AD. 10,11 Previously, we have shown in a rat model of AD, by directly injecting Ab fibrils into the hippocampal regions, that lithium treatment resulted in the improvement of spatial memory and in decreased glial inflammatory reaction, most likely by the activation of the Wnt signaling pathway. 12 Moreover, therapeutic concentrations of lithium interfere with the APP cleavage at the g-secretase level and reduce the amyloid burden in the brain of transgenic mice models of AD.…”

Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

“…In addition, AβO-induced GSK3β over-activity could lead to glutamate receptor internalization, spine retraction, LTP blockage, and LTD facilitation [4,49] . The blockade of either GSK3β expression or activity decreased Aβ production and plaque accumulation [50] , improved performance in memory tests, preserved the dendritic structure, and reduced the Tau-dependent pathology in AD transgenic models [51,52] . In our study, we found that atorvastatin pretreatment prevented AβO-induced decreases in Ser-9 phosphorylation in hippocampal neurons, suggesting decreased activity of GSK3β.…”