. Loss of Adaptive Myelination Contributes to Methotrexate Chemotherapy-Related Cognitive Impairment. Neuron. 2019 May 10; PubMed.

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  1. This is a very interesting paper providing further evidence, in a mouse model, for how chemotherapy—specifically methotrexate/MTX—could affect cognition, and how this involves multiple glial cell types, eventually leading to defective adaptive myelination. To induce and measure adaptive myelination, the authors used an elegant optogenetics strategy based on optical channelrhodopsin stimulation in cortical neurons. Only quite recently, the same group identified that MTX negatively affects oligodendrocytes and their precursors, and that a tri-glial mechanism explains some of these negative effects of chemotherapy on the brain (Gibson et al., 2019). The current study also identifies that under methotrexate treatment, microglia appear, at least partly, responsible for this effect on myelination by decreasing neuronal expressed/secreted BDNF.

    One question that comes to mind that is not addressed in this paper is how microglia then affect BDNF expression. Perhaps they could phagocytize the secreted vesicles that contain BDNF. The paper adds to a growing list of reported beneficial effects of depletion of microglia under specific disease conditions in mouse models.

    There is also quite strong evidence that suggests that there are beneficial effects of microglia on myelination mediated by yet-to-be-identified mechanisms. We recently showed that, in rare human infantile and adult-onset white matter diseases caused by bi-allelic and homozygous or heterozygous mutations in CSF1R, there is an almost complete loss and a reduced density of microglia and regional loss (Oosterhof et al., 2019; Oosterhof et al., 2018). We hypothesize that in these cases, insufficient microglia numbers or activity could lead to defective myelination and/or loss of myelin. This would suggest a more trophic, supportive role of microglia which could be lost, explaining the detrimental effect on the myelin.

    Evidence of such a beneficial/positive role of microglia in myelination is provided by several studies, for example one, using a mouse model, that identified that the growth factor IGF1 secreted by microglia is needed for myelination in postnatal brain development (Wlodarczyk et al., 2017).  Another study showed a role of microglia in adult myelination, by using microglia depletion by inhibition of CSF1R (Hagemeyer et al., 2017). Both studies provide strong evidence that microglia affect under homeostasis the oligodendrocytes and their progenitor cells (OPCs). Other recent work shows that replenishing microglia in mouse with homozygous Csf1r mutations, which have essentially no microglia and severe brain defects, rescues some of these defects as viability of these mice is strongly increased (Bennett et al., 2018, Neuron).

    In human, transplantation of hematopoietic cells in metachromatic leukodystrophy can stabilize disease and increase burden-free survival (van Rappard et al., Blood, 2016). Anecdotal evidence exists that such transplantations also could benefit patients with heterozygous CSF1R mutations, which could possibly occur by enhancing brain macrophage or microglia function.

    Clearly, strong evidence exists that enhancing as well as reducing microglia activity can be beneficial, but importantly, the specific circumstances, i.e. brain region, age of patient, type of disease, and the state of the microglia, could prove critical in determining the success of such approaches. That said, Geraghty et al. in the current work appear to neatly bypass these complex issues by directly acting at the downstream consequence, and provide a pharmacological means to enhance adaptive myelination, by acting on the TrkB receptor on OPCs.

    References:

    . Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment. Cell. 2019 Jan 10;176(1-2):43-55.e13. Epub 2018 Dec 6 PubMed.

    . Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia. Am J Hum Genet. 2019 Mar 29; PubMed.

    . Colony-Stimulating Factor 1 Receptor (CSF1R) Regulates Microglia Density and Distribution, but Not Microglia Differentiation In Vivo. Cell Rep. 2018 Jul 31;24(5):1203-1217.e6. PubMed.

    . A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J. 2017 Nov 15;36(22):3292-3308. Epub 2017 Sep 28 PubMed.

    . Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol. 2017 Sep;134(3):441-458. Epub 2017 Jul 6 PubMed.

    . A Combination of Ontogeny and CNS Environment Establishes Microglial Identity. Neuron. 2018 Jun 27;98(6):1170-1183.e8. Epub 2018 May 31 PubMed.

    . Efficacy of hematopoietic cell transplantation in metachromatic leukodystrophy: the Dutch experience. Blood. 2016 Jun 16;127(24):3098-101. Epub 2016 Apr 26 PubMed.

    View all comments by Tjakko Van Ham
  2. This paper, combined with the Monje lab’s recent Cell paper (Gibson et al., 2018), elegantly highlights the complexity of cellular interactions in toxicity/disease states, and place microglia as the major effector cell type that has broad effects on astrocytes, neurons, and oligodendrocytes following chemotherapy.

    The previous paper demonstrated that MTX treatment led to changes in microglial activation states that in turn regulated astrocyte signaling and function, ultimately causing deficits in myelination and leading to cognitive impairments. This follow-up study identifies how MTX-mediated microglial changes downregulate neuronal BDNF levels, which in turn reduce activity-dependent myelination via inhibition of OPC proliferation. Notably, depletion of microglia via the CSF1R inhibitor PLX5622 reversed all the phenotypes associated with MTX administration (cognitive impairments, changes in astrocyte phenotypes, myelination, and reductions in BDNF).

    Overall, these results shed light on the upstream causes of "chemo-brain" and suggest that targeting of microglia would be broadly beneficial. The challenge will be on how to target microglia in the human brain, as microglial depletion in humans is probably premature. 

    Of relevance to Alzheimer's disease and other brain disorders, these studies show that cells do not work alone in the brain, but have highly complex relationships with one another, and that understanding and dissecting these relationships is challenging but critical. How glial cells can regulate neuronal form and function may be integral to the pathogenesis of diseases such as AD.

    References:

    . Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment. Cell. 2019 Jan 10;176(1-2):43-55.e13. Epub 2018 Dec 6 PubMed.

    View all comments by Kim Green

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  1. Microglia Instigate ‘Chemofog’ by Squelching Myelination