Inhibition of glycogen synthase kinase-3β downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A

Martin, Ludovic; Magnaudeix, Amandine; Esclaire, Françoise; Yardin, Catherine; Terro, Faraj

doi:10.1016/j.brainres.2008.11.057

Cited by 54 publications

(34 citation statements)

References 52 publications

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“…Both lithium and BIO are reported to decrease total tau protein levels in addition to their inhibitory effects of GSK in cultured neurons. 42 In agreement with previous reports, 41,42 −26%, P=0.048; Supplementary Figures 10c and d) that may be the mechanism for its ability to increase neuronal iron levels.…”

Section: Lithium Induces Tau-mediated Iron Accumulation In Neuronal Csupporting

confidence: 92%

“…40 Nevertheless, lowering total tau expression is still being explored as a potential treatment for AD, and lithium is still being considered as a treatment option as it lowers both tau protein and mRNA levels in cultured cortical neurons. 41,42 Supporting this concept, long-term (5 months) lithium treatment of PrP T44 tau transgenic mice resolved tau aggregates by promoting ubiquitination and degradation of tau, rather than altering GSK-3 activity. 36 We, and others, have reported concerns that lowering levels of brain tau could induce agedependent neurodegeneration.…”

Section: Introductionmentioning

confidence: 97%

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Lithium suppression of tau induces brain iron accumulation and neurodegeneration

et al. 2016

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Lithium is a first-line therapy for bipolar affective disorder. However, various adverse effects, including a Parkinson-like hand tremor, often limit its use. The understanding of the neurobiological basis of these side effects is still very limited. Nigral iron elevation is also a feature of Parkinsonian degeneration that may be related to soluble tau reduction. We found that magnetic resonance imaging T 2 relaxation time changes in subjects commenced on lithium therapy were consistent with iron elevation. In mice, lithium treatment lowers brain tau levels and increases nigral and cortical iron elevation that is closely associated with neurodegeneration, cognitive loss and parkinsonian features. In neuronal cultures lithium attenuates iron efflux by lowering tau protein that traffics amyloid precursor protein to facilitate iron efflux. Thus, tauand amyloid protein precursor-knockout mice were protected against lithium-induced iron elevation and neurotoxicity. These findings challenge the appropriateness of lithium as a potential treatment for disorders where brain iron is elevated (for example, Alzheimer's disease), and may explain lithium-associated motor symptoms in susceptible patients.

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Section: Lithium Induces Tau-mediated Iron Accumulation In Neuronal Csupporting

confidence: 92%

Section: Introductionmentioning

confidence: 97%

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

et al. 2016

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“…Cocrystal structures showed a direct interaction of 6BIO within the ATP-binding pocket of GSK3b (15). Along this line, 6BIO has been used to maintain pluripotency of human embryonic stem cells (23), to prevent GSK3b-induced glucocorticoid bone loss (24), and to counteract tau protein aggregation in tauopathies such as Alzheimer disease (25). Recently, to extend the therapeutic application of 6BIO beyond its usage as a GSK3b inhibitor, a panel of various isolated kinases has been tested for inhibition by 6BIO (21,26).…”

Section: Discussionmentioning

confidence: 99%

Indirubin Derivative 6BIO Suppresses Metastasis

et al. 2013

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While metastasis is the chief cause of cancer mortality, there nonetheless remains a lack of antimetastatic therapies that are clinically available. In this study, we present the indirubin derivative 6-bromo-indirubin-3 0 -oxime (6BIO) as a promising antimetastatic agent. 6BIO strongly reduced formation of lung metastasis in the well-established 4T1 mouse model of aggressive breast cancer. Several major hallmarks of the metastatic process were affected by subtoxic concentrations of 6BIO, which inhibited adhesion, migration, and invasion of a variety of metastatic cell types in vitro. Mechanistic analyses focused on known targets of 6BIO, which were silenced by this compound. Unexpectedly, RNAi-mediated silencing of glycogen synthase kinase 3b (GSK3b) and phosphoinositide-dependent protein kinase 1 (PDK1), both modulators of cellular metastasis targeted by 6BIO, were not found to affect invasive migration in this study. Instead, the Jak/STAT3 signaling pathway appeared to play a major role through modulation of its downstream migration regulators Cterminal tensin-like protein and matrix metalloproteinase 2. However, PDK1 and GSK3b contributed to the overall response to 6BIO, as silencing of all three pathways resulted in almost complete inhibition of migration, phenocopying the 6BIO response. Taken together, our findings illustrate the antimetastatic activity of 6BIO on the basis of its ability to simultaneously inhibit several kinase cascades involved in metastasis of cancer cells, supporting the concept of "polypharmacology" in developing drugs to attack metastasis, the most deadly aspect of cancer. Cancer Res; 73(19); 6004-12. Ó2013 AACR.

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“…In the rat brain, lithium treatment not only increased PP2A activity (Tsuji et al, 2003), but also decreased tau phosphorylation, which in turn, facilitated tau destruction (Rametti et al, 2004). Finally, the fact that blockade of PP2A activity in cultured neurons reversed lithium-induced down-regulation of total tau proteins mediated by GSK-3b inhibition (Martin et al, 2009) suggests that PP2A is involved in lithium's action.…”

Section: Admentioning

confidence: 96%

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

et al. 2013

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Inhibition of glycogen synthase kinase-3β downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A

Cited by 54 publications

References 52 publications

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

Indirubin Derivative 6BIO Suppresses Metastasis

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

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