Lithium inhibits Alzheimer's disease‐like tau protein phosphorylation in neurons

Muñoz-Montaño, Juan Ramón; Moreno, Francisco J.; Ávila, Jesús; Díaz‐Nido, Javier

doi:10.1016/s0014-5793(97)00688-1

Cited by 300 publications

(195 citation statements)

References 40 publications

(42 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: 90%

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: 90%

Neuroplasticity and cellular resilience in mood disorders

et al. 2000

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“…121 Tau has been identified as an important substrate of GSK-3 in vitro and in vivo and can be phosphorylated at primed (e.g., T231) and unprimed epitopes (PHF-1, Tau-1, and AT8). [122][123][124] Priming involves the prior phosphorylation of a serine or threonine residue, four amino acids C-terminal to the target phosphorylation site. 125 Active GSK-3 was detected in pretangle neurons and NFTs in AD brains, and coexpression of the GSK-3 homolog shaggy with tau led to tau hyperphosphorylation, filamentous tau aggregation, and neurotoxicity in Drosophila fruit fly.…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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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 inhibits Alzheimer's disease‐like tau protein phosphorylation in neurons

Cited by 300 publications

References 40 publications

Neuroplasticity and cellular resilience in mood disorders

Neuroplasticity and cellular resilience in mood disorders

Tau-Based Treatment Strategies in Neurodegenerative Diseases

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

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