Loss of adaptive myelination contributes to methotrexate chemotherapy-related cognitive impairment
Open accessAbstract
Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.
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Microglia become persistently reactive following exposure to certain chemotherapy drugs, after cranial radiation, or after systemic inflammatory challenge with low-dose lipopolysaccharide.
“Microglia, brain-resident macrophages, become persistently reactive following exposure to certain chemotherapy drugs, after cranial radiation, or after systemic inflammatory challenge with low-dose lipopolysaccharide (Geraghty et al., 2019; Gibson et al., 2019; Monje et al., 2002, 2003, 2007).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Geraghty et al., 2019
Reactive microglia and brain-infiltrating macrophages impair mechanisms of cellular homeostasis and plasticity such as the ongoing generation of myelin-forming oligodendrocytes, myelin plasticity, and new neuron generation in the hippocampus.
“Reactive microglia and brain-infiltrating macrophages impair mechanisms of cellular homeostasis and plasticity such as the ongoing generation of myelin-forming oligodendrocytes (Gibson et al., 2019), myelin plasticity (Geraghty et al., 2019), and new neuron generation in the hippocampus (Monje et al., 2002, 2003, 2007).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Geraghty et al., 2019
This complex cellular dysregulation is thought to contribute importantly to cognitive impairment.
“This complex cellular dysregulation is thought to contribute importantly to cognitive impairment, and anti-inflammatory strategies correct this multicellular dysregulation and rescue cognition in disease states such as those occurring after exposure to neurotoxic cancer therapies (Geraghty et al., 2019; Gibson et al., 2019; Monje et al., 2003) and in aging (Villeda et al., 2011).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Geraghty et al., 2019
Anti-inflammatory strategies correct multicellular dysregulation and rescue cognition in disease states such as those occurring after exposure to neurotoxic cancer therapies and in aging.
“This complex cellular dysregulation is thought to contribute importantly to cognitive impairment, and anti-inflammatory strategies correct this multicellular dysregulation and rescue cognition in disease states such as those occurring after exposure to neurotoxic cancer therapies (Geraghty et al., 2019; Gibson et al., 2019; Monje et al., 2003) and in aging (Villeda et al., 2011).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Geraghty et al., 2019
White-matter-selective/enriched microglial reactivity is associated with impaired hippocampal neurogenesis, dysregulation of the oligodendroglial lineage, and myelin loss in other disease contexts.
“Such neuroinflammatory changes—particularly white-matter-selective/enriched microglial reactivity—are associated with impaired hippocampal neurogenesis, dysregulation of the oligodendroglial lineage, and myelin loss in other disease contexts (Geraghty et al., 2019; Gibson et al., 2019; Guttenplan et al., 2021; Liddelow et al., 2017; Monje et al., 2003; Villeda et al., 2011).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Geraghty et al., 2019
Changes in myelin sheath thickness relative to axon diameter (g ratio) were not conclusively identified in remaining myelin sheaths after mild respiratory COVID, in contrast to methotrexate chemotherapy exposure.
“In contrast to methotrexate chemotherapy exposure (Geraghty et al., 2019; Gibson et al., 2019), changes in myelin sheath thickness relative to axon diameter (g ratio) were not conclusively identified in the remaining myelin sheaths after mild respiratory COVID (Figures S7C–S7F).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Geraghty et al., 2019
Preclinical studies in disease models sharing features with the cellular dysregulation observed here after mild respiratory COVID have identified anti-inflammatory and neuro-regenerative strategies that restore neural plasticity and rescue cognition.
“Preclinical studies in disease models that share numerous features with the cellular dysregulation observed here after mild respiratory COVID have identified anti-inflammatory and neuro-regenerative strategies that restore neural plasticity and rescue cognition (Ayoub et al., 2020; Geraghty et al., 2019; Gibson et al., 2019; Monje et al., 2003; Villeda et al., 2011).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Geraghty et al., 2019
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- Authors
- Geraghty, A. C., Gibson, E. M., Ghanem, R. A., Greene, J. J., Ocampo, A., Goldstein, A. K., Ni, L., Yang, T., Marton, R. M., Paşca, S. P., Greenberg, M. E., Longo, F. M., & Monje, M.
- Affiliations
- Stanford University (US)
- Stanford Medicine (US)
- Harvard University (US)
- Corresponding author
- Monje, Michelle
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 103
- Issue
- 2
- Pages
- 250-265.e8
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6697075
- OpenAlex
- W2946168453
- Cited by
- 288
- References
- 104
- Citations by year
- 2026: 34 · 2025: 50 · 2024: 35 · 2023: 43 · 2022: 41 · 2021: 40 · 2020: 32 · 2019: 10 · 2015: 1
- FWCI
- 22.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DP1 NS111132)
- California Institute for Regenerative Medicine (RN3-06510, RB4-06093)
- National Institute of Neurological Disorders and Stroke (R01 NS092597, R37 NS028829)
- Stanford Maternal and Child Health Research Institute
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- chemotherapy-induced cognitive impairment, methotrexate, activity-dependent myelination, microglial activation, BDNF/TrkB signaling, oligodendrocyte precursor cells, myelin plasticity, cognitive impairment, TrkB agonist, glial dysfunction
- MeSH terms
- Oligodendrocyte Precursor Cells, Channelrhodopsins, Animals, Cerebral Cortex, Cognition Disorders, Disease Models, Animal, Humans, Immunosuppressive Agents, Luminescent Proteins, Membrane Glycoproteins, Methotrexate, Mice, Inbred C57BL, Mice, Transgenic, Myelin Sheath, Organic Chemicals, Protein-Tyrosine Kinases, Urea, Signal Transduction, Brain-Derived Neurotrophic Factor, Receptor, trkB, Recognition, Psychology, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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