Lithium Reduces Tau Phosphorylation by Inhibition of Glycogen Synthase Kinase-3

Hong, Ming; Chen, Daniel C.; Klein, Peter S.; Lee, Virginia M.‐Y.

doi:10.1074/jbc.272.40.25326

Cited by 430 publications

(315 citation statements)

References 62 publications

(59 reference statements)

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“…118 Although many of the studies have utilized lithium concentrations in excess of those utilized therapeutically, the available data suggest that lithium, at concentrations of ෂ1 mM does, indeed, reduce tau phosphorylation. 118,[123][124][125] Overall, the data suggest that in addition to bcl-2 upregulation, inhibition of GSK-3␤ by lithium may also afford protection against the cell death induced by various stimuli. 126 In view of the important role of GSK-3␤ in cell survival, a study was undertaken to determine if other mood stabilizers also regulate GSK3␤.…”

Section: Inhibition Of Glycogen Synthase Kinase 3␤ (Gsk-3␤) May Also mentioning

confidence: 93%

Neuroplasticity and cellular resilience in mood disorders

et al. 2000

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Although mood disorders have traditionally been regarded as good prognosis diseases, a growing body of data suggests that the long-term outcome for many patients is often much less favorable than previously thought. Recent morphometric studies have been investigating potential structural brain changes in mood disorders, and there is now evidence from a variety of sources demonstrating significant reductions in regional CNS volume, as well as regional reductions in the numbers and/or sizes of glia and neurons. Furthermore, results from recent clinical and preclinical studies investigating the molecular and cellular targets of mood stabilizers and antidepressants suggest that a reconceptualization about the pathophysiology and optimal long-term treatment of recurrent mood disorders may be warranted. It is proposed that impairments of neuroplasticity and cellular resilience may underlie the pathophysiology of mood disorders, and further that optimal long-term treatment for these severe illnesses may only be achieved by the early and aggressive use of agents with neurotrophic/ neuroprotective effects. It is noteworthy that lithium, valproate and antidepressants indirectly regulate a number of factors involved in cell survival pathways including CREB, BDNF, bcl-2 and MAP kinases, and may thus bring about some of their delayed long-term beneficial effects via underappreciated neurotrophic effects. The development of novel treatments which more directly target molecules involved in critical CNS cell survival and cell death pathways have the potential to enhance neuroplasticity and cellular resilience, and thereby modulate the long-term course and trajectory of these devastating illnesses. Molecular Psychiatry (2000) 5, 578-593.Keywords: atrophy; cell death; neuroprotection; lithium; bcl-2; MAP kinase; neurite; neurotrophic; neurogenesis; N-acetylaspartate; gray matter There is mounting evidence that recurrent mood disorders-once considered 'good prognosis diseases'-are, in fact, often very severe and life-threatening illnesses. Recurrent mood disorders can have devastating long-term effects, and the cost of these illnesses in terms of human suffering, productivity and health care is enormous. Suicide is the cause of death in 10-20% of individuals, and in addition to suicide, mood disorders are associated with many other deleterious health-related effects. 1-5 Indeed, a recent study which controlled for physical illness, smoking and alcohol consumption found that the magnitude of the increased mortality risk conferred by the presence of high depressive symptoms was similar to that of stroke and congestive heart failure. 5 Not surprisingly, the costs associated with disability and premature death represent an economic burden of tens of billions of dollars annually in the United States alone. 1,6,7 It is now recognized that, for many patients, the long-term outCorrespondence: HK Manji, MD,

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Section: Inhibition Of Glycogen Synthase Kinase 3␤ (Gsk-3␤) May Also mentioning

confidence: 93%

Neuroplasticity and cellular resilience in mood disorders

et al. 2000

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“…Lithium is useful in this regard, because it is a selective inhibitor of GSK3␤ (44, 45), a finding substantiated by an examination of 24 kinases, which showed that GSK3␤, and the closely related GSK3␣, to be the only kinases substantially inhibited by lithium (46). Extensive studies have clearly documented that several of lithium's prominent effects, such as inhibition of the phosphorylation of the microtubule-associated protein tau, increased levels of ␤-catenin, and protection from GSK3␤-facilitated apoptosis, are directly dependent on lithium's inhibition of GSK3␤ (24,(47)(48)(49); reviewed in Refs. 21 and 50).…”

mentioning

confidence: 93%

Central Role of Glycogen Synthase Kinase-3β in Endoplasmic Reticulum Stress-induced Caspase-3 Activation

Lee

Sarno

Jope

2002

Journal of Biological Chemistry

255

240

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Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca 2؉ -ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3␤ (GSK3␤). Activation of GSK3␤ was obligatory for thapsigargin-induced activation of caspase-3, because inhibition of GSK3␤ by expression of dominantnegative GSK3␤ or by the GSK3␤ inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3␤ by inducing dephosphorylation of phospho-Ser-9 of GSK3␤, a phosphorylation that normally maintains GSK3␤ inactivated. Caspase-3 activation induced by thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3␤ with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3␤ through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.

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“…60 In addition, GSK-mediated phosphorylation of MAP-B and tau proteins regulate microtubule assembly and stabilization at synapses. 57,[61][62][63] Clinical studies have demonstrated that specific GSK-3 inhibitors mimic the therapeutic action of mood stabilizers and might therefore be plausible drugs in treating bipolar patients. 64 Crosstalk between PKC and GSK-3b signaling pathways Certain PKC isoforms have been shown to phosphorylate and inactivate GSK-3b in vitro.…”

Section: Lithium and Wnt Signaling Pathwaymentioning

confidence: 99%

Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks

2003

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The clinical efficacy of lithium in the prophylaxis of recurrent affective episodes in bipolar disorder is characterized by a lag in onset and remains for weeks to months after discontinuation. Thus, the long-term therapeutic effect of lithium likely requires reprogramming of gene expression. Protein kinase C and glycogen synthase kinase-3 signal transduction pathways are perturbed by chronic lithium at therapeutically relevant concentrations and have been implicated in modulating synaptic function in nerve terminals. These signaling pathways offer an opportunity to model critical signals for altering gene expression programs that underlie adaptive responses of neurons to long-term lithium exposure. While the precise physiological events critical for the clinical efficacy of lithium remain unknown, we propose that linking lithium-responsive genes as a regulatory network will provide a strategy to identify signature gene expression patterns that distinguish between therapeutic and nontherapeutic actions of lithium.

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Lithium Reduces Tau Phosphorylation by Inhibition of Glycogen Synthase Kinase-3

Cited by 430 publications

References 62 publications

Neuroplasticity and cellular resilience in mood disorders

Neuroplasticity and cellular resilience in mood disorders

Central Role of Glycogen Synthase Kinase-3β in Endoplasmic Reticulum Stress-induced Caspase-3 Activation

Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks

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