Dimethyl Sulfoxide Induces Both Direct and Indirect Tau Hyperphosphorylation

Julien, Carl; Marcouiller, François; Bretteville, Alexis; Khoury, Noura B. El; Baillargeon, Joanie; Hébert, Sébastien S.; Planel, Emmanuel

doi:10.1371/journal.pone.0040020

Cited by 27 publications

(17 citation statements)

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“…This can be readily explained as it is well documented that cell lines are more resistant to insults than primary cell cultures (41). High concentrations of DMSO (>10% v/v) have previously been shown to induce toxicity (5, 6, 40) through plasma membrane pore formation (23, 24). In the present study, we describe a new mechanism by which DMSO induces neuronal death at significantly lower concentrations than previous reported.…”

Section: Discussionmentioning

confidence: 99%

“…6). Moreover, intraperitoneal injections of 4 ml/kg of DMSO (10% v/v) have been found to induce Tau hyperphosphorylation in the brains of C57/129 mice (5). We believe our data suggest that DMSO could be used as a new, inexpensive model for retinal neuron cell death and neurodegeneration in vivo, with the opportunity of providing a rapid assessment of neuroprotective strategies.…”

Section: Discussionmentioning

confidence: 99%

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Unexpected low‐dose toxicity of the universal solvent DMSO

et al. 2013

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Dimethyl sulfoxide (DMSO) is an important aprotic solvent that can solubilize a wide variety of otherwise poorly soluble polar and nonpolar molecules. This, coupled with its apparent low toxicity at concentrations <10%, has led to its ubiquitous use and widespread application. Here, we demonstrate that DMSO induces retinal apoptosis in vivo at low concentrations (5 μl intravitreally dosed DMSO in rat from a stock concentration of 1, 2, 4, and 8% v/v). Toxicity was confirmed in vitro in a retinal neuronal cell line, at DMSO concentrations >1% (v/v), using annexin V, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and AlamarBlue cell viability assays. DMSO concentrations >10% (v/v) have recently been reported to cause cellular toxicity through plasma membrane pore formation. Here, we show the mechanism by which low concentrations (2-4% DMSO) induce caspase-3 independent neuronal death that involves apoptosis-inducing factor (AIF) translocation from mitochondria to the nucleus and poly-(ADP-ribose)-polymerase (PARP) activation. These results highlight safety concerns of using low concentrations of DMSO as a solvent for in vivo administration and in biological assays. We recommend that methods other than DMSO are employed for solubilizing drugs but, where no alternative exists, researchers compute absolute DMSO final concentrations and include an untreated control group in addition to DMSO vehicle control to check for solvent toxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Unexpected low‐dose toxicity of the universal solvent DMSO

et al. 2013

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“…It has been reported that DMSO exhibits beneficial effects in other injury models, however the beneficial effects of DMSO are not seen consistently across studies and there is little consensus about how DMSO might act in the injured brain (Jacob and de la Torre, 2009; Julien et al, 2012). Importantly, our data show that the cell division blockers inhibit the rate of recovery despite the facilitative effects of the DMSO vehicle in which the drug is delivered (Figure 9A and Table 2).…”

Section: Discussionmentioning

confidence: 99%

Neurogenesis is required for behavioral recovery after injury in the visual system of Xenopus laevis

McKeown¹,

Sharma²,

Sharipov³

et al. 2013

J of Comparative Neurology

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Non-mammalian vertebrates have a remarkable capacity to regenerate brain tissue in response to CNS injury. Nevertheless, it is not clear whether animals recover lost function after injury or whether injury-induced cell proliferation mediates recovery. We address these questions using the visual system and visually-guided behavior in Xenopus laevis tadpoles. We established a reproducible means to produce a unilateral focal injury to optic tectal neurons without damaging retinotectal axons. We then assayed a tectally-mediated visual avoidance behavior to evaluable behavioral impairment and recovery. Focal ablation of part of the optic tectum prevents the visual avoidance response to moving stimuli. Animals recover the behavior over the week following injury. Injury induces a burst of proliferation of tectal progenitor cells based on phospho-histone H3 immunolabeling and experiments showing that Musashi-immunoreactive tectal progenitors incorporate the thymidine analog iododeoxyuridine after injury. Pulse chase experiments indicate that the newly-generated cells differentiate into N-β–tubulin-immunoreactive neurons. Furthermore, in vivo time-lapse imaging shows that Sox2-expressing neural progenitors divide in response to injury and generate neurons with elaborate dendritic arbors. These experiments indicate that new neurons are generated in response to injury. To test if neurogenesis is necessary for recovery from injury, we blocked cell proliferation in vivo and found that recovery of the visual avoidance behavior is inhibited by drugs that block cell proliferation. Moreover, behavioral recovery is facilitated by changes in visual experience that increase tectal progenitor cell proliferation. Our data indicate that neurogenesis in the optic tectum is critical for recovery of visually-guided behavior after injury.

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“…Same b-actin band are presented for p-tau (a) and total tau (b). Data are presented as mean ± S. E. M., One-way ANOVA, n = 3 hyperphosphorylation of tau in animals that developed hypothermia, independently of kinase and phosphatase activity (Dong et al 2012;Julien et al 2012). Interestingly, reversible tau phosphorylation in the hippocampus is observed after 1 h in animals acutely subjected to cold conditions, followed by a second peak of tau phosphorylation at 6 h (Feng et al 2005), suggesting the possibility that kinase/phosphatase dynamics regulate the initial rapid turnover of p-tau, by activation of indirect pathways or via direct activity of phosphatases, while transcription and protein degradation may regulate the second, later peak of tau phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

The Co-chaperone BAG2 Mediates Cold-Induced Accumulation of Phosphorylated Tau in SH-SY5Y Cells

et al. 2015

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Inclusions of phosphorylated tau (p-tau) are a hallmark of many neurodegenerative disorders classified as "tauopathy," of which Alzheimer's disease is the most prevalent form. Dysregulation of tau phosphorylation disrupts neuron structure and function, and hyperphosphorylated tau aggregates to form neurotoxic inclusions. The abundance of ubiquitin in tau inclusions suggests a defect in ubiquitin-mediated tau protein degradation by the proteasome. Under the temperature of 37 °C, the co-chaperone BAG2 protein targets phosphorylated tau for degradation via by a more-efficient, ubiquitin-independent pathway. In both in vivo and in vitro studies, cold exposure induces the accumulation of phosphorylated tau protein. The SH-SY5Y cell line differentiates into neuron-like cells on treatment with retinoic acid and is an established model for research on the effects of cold on tau phosphorylation. The aim of the present study was to investigate whether BAG2 mediates the cold-induced accumulation of phosphorylated tau protein. Our findings show that cold exposure causes a decrease in BAG2 expression in undifferentiated cells. Conversely, BAG2 expression is increased in differentiated cells exposed to cold. Further, undifferentiated cells exposed to cold had an increased proportion of p-tau to total tau, suggesting an accumulation of p-tau that is consistent with decreased levels of BAG2. Overexpression of BAG2 in cold-exposed undifferentiated cells restored levels of p-tau to those of 37 °C undifferentiated control. Interestingly, although BAG2 expression increased in differentiated cells, this increase was not accompanied by a decrease in the proportion of p-tau to total tau. Further, overexpression of BAG2 in cold exposed differentiated cells showed no significant difference in p-tau levels compared to 37 °C controls. Taken together, these data show that expression of BAG2 is differently regulated in a differentiation-dependent context. Our results suggest that repression of BAG2 expression or BAG2 activity by cold-sensitive pathways, as modeled in undifferentiated and differentiated cells, respectively, may be a causal factor in the accumulation of cytotoxic hyperphosphorylated tau protein via restriction of BAG2-mediated clearance of cellular p-tau.

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Dimethyl Sulfoxide Induces Both Direct and Indirect Tau Hyperphosphorylation

Cited by 27 publications

References 50 publications

Unexpected low‐dose toxicity of the universal solvent DMSO

Unexpected low‐dose toxicity of the universal solvent DMSO

Neurogenesis is required for behavioral recovery after injury in the visual system of Xenopus laevis

The Co-chaperone BAG2 Mediates Cold-Induced Accumulation of Phosphorylated Tau in SH-SY5Y Cells

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