We can now add myelination to the list of critical functions put on hold by cantankerous microglia. A paper published May 10 in Neuron reported that in mice treated with the widely used chemotherapy drug methotrexate, microglia became activated and, like so many wet blankets, doused neuronal expression of brain-derived growth factor (BDNF). This stifled the development of oligodendrocytes, thwarting myelination. As a consequence, the mice suffered memory loss, modeling the phenomenon known as “chemo-fog” in cancer patients. Led by Michelle Monje at Stanford University, the researchers restored myelination and memory by boosting BDNF signaling in oligodendrocytes with a small-molecule drug. They propose that tempering microglial activation could have a similar effect.
- Methotrexate activates microglia, leading neurons to reduce BDNF expression.
- Low BDNF reduces activity-dependent myelination by oligodendrocytes, and triggers memory loss.
- The small molecule LM22A-4 restores myelination and cognition.
The study casts reactive microglia as blockers of myelination, and raises the possibility that these cells could cause similar problems in other contexts in which they are aberrantly activated, such as in neurodegenerative disease, Monje noted.
Oligodendrocytes form the fatty myelin sheath that insulates axons in the brain and enables rapid neuronal signaling. Although axons become myelinated by default during development, in recent years, researchers have discovered that neuronal activity can also trigger myelination throughout life. This activity-dependent myelination is thought to facilitate structural plasticity in the brain (Gibson et al., 2014; Bechler et al., 2015; Mount and Monje, 2017). Earlier this year, Monje’s group reported that in mice treated with methotrexate, activated microglia soured this form of myelination by somehow derailing the development of oligodendrocytes (Gibson et al., 2019).
In their current study, first author Anna Geraghty and colleagues fleshed out the pathway. They used an optogenetic mouse model with an implanted probe to stimulate premotor neurons that project axons into the corpus callosum—the dense white-matter tract that separates the hemispheres of the brain. Stimulating these neurons promoted proliferation of nearby oligodendrocyte progenitor cells (OPCs), and the myelin sheath thickened. Methotrexate blocked this activity-dependent myelination, unless microglia were first depleted with the CSF-1R inhibitor PLX5622. This suggested that microglia somehow facilitate methotrexate’s negative impacts on myelination, but how?
The scientists hypothesized that BDNF might play a role, as a recent study linked a BDNF polymorphism with decreased risk for cognitive impairment after chemotherapy in women (Ng et al., 2016). Indeed, they found that in response to methotrexate treatment, BDNF mRNA and protein plummeted in the deep layers of the mice’s frontal cortices. Depleting microglia prevented this dip in BDNF, suggesting that microglia somehow hush BDNF expression in neurons.
BDNF signals through the TrkB receptor on OPCs, triggering their proliferation and ultimate differentiation into functional oligodendrocytes. Using an intricate combination of mouse models, the researchers pieced together the pathway leading from methotrexate to flagging myelin production. They reported that under healthy conditions, neural activity stimulates BDNF expression, which signals through the TrKB receptor on OPCs, leading to their proliferation and ultimately, a boost in myelination. Methotrexate derails this by activating microglia, which somehow block neurons from producing BDNF. The loss of myelination prevented mice from distinguishing novel from familiar objects, a measure of memory loss.
Finally, the researchers found that they could circumvent the testy microglia and their muted neuronal bystanders by stimulating OPCs directly, using the small molecule TrkB receptor agonist LM22A-4. The treatment not only restored activity-dependent myelination, but also prevented memory loss in response to methotrexate.
How microglia turn down neuronal BDNF production in response to methotrexate is unclear, Monje said. In response to methotrexate treatment, microglia appear to shift from a more trophic, homeostatic state to an activated, neurotoxic one. Although this general state change has been noted in neurodegenerative disease as well, Monje pointed out that microglia likely undergo distinct changes depending on the disease setting. She proposed that despite these differences, microglia could similarly shut down BDNF expression in the context of other pathologies. The growth factor is thought to play a role in AD, as a polymorphism in the gene hastens cognitive decline in people with Aβ accumulation (Oct 2014 news). Whether flagging activity-dependent myelination mediates this cognitive effect is unclear, although white-matter abnormalities have been associated with AD as well (for review, see Nasrabady et al., 2018).
“This speaks to the notion that no microglia is far better than bad microglia,” noted Kim Green at the University of California, Irvine, who pioneered the use of CSF-1R inhibitors to deplete microglia (Apr 2014 news). His lab reported similar beneficial effects of booting the immune cells following radiotherapy (Acharya et al., 2016). “Overall, these results shed light on the upstream causes of ‘chemo-brain’ and suggest that targeting of microglia would be broadly beneficial,” Green wrote, cautioning that more research is needed before attempting to do so in humans. “How glial cells can regulate neuronal form and function may be integral to the pathogenesis of diseases such as AD,” he added.
However, Tjakko Van Ham of Erasmus University in Rotterdam noted that although microglial depletion is beneficial in certain settings, other data paint a picture of microglia as supporting myelin (for review, see Miron, 2017). He co-authored a case study of an infant with a homozygous mutation in CSF-1R, who was born with profound white-matter abnormalities, including a complete lack of the corpus callosum (Apr 2019 news). At autopsy, the infant’s brain was devoid of microglia, suggesting that the cells play a key role in supporting the development of white-matter structures. “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,” Van Ham wrote to Alzforum.
Monje told Alzforum that her lab is investigating whether the microglia that repopulate the brain following depletion regain a calm and myelin-friendly state, even in mice previously treated with methotrexate. She proposed the TrkB agonist and microglial depletion as complementary strategies for warding off chemo-fog, and perhaps for other neurological disorders.—Jessica Shugart
- Do Neurotrophin and ApoE Together Exacerbate Alzheimer's?
- Microglial Magic: Drug Wipes Them Out, New Set Appears
- Life Without Microglia: Rare Cases of CSF-1R Mutations Paint a Grim Picture
- Gibson EM, Purger D, Mount CW, Goldstein AK, Lin GL, Wood LS, Inema I, Miller SE, Bieri G, Zuchero JB, Barres BA, Woo PJ, Vogel H, Monje M. Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science. 2014 May 2;344(6183):1252304. Epub 2014 Apr 10 PubMed.
- Bechler ME, Byrne L, Ffrench-Constant C. CNS Myelin Sheath Lengths Are an Intrinsic Property of Oligodendrocytes. Curr Biol. 2015 Sep 21;25(18):2411-6. Epub 2015 Aug 27 PubMed.
- Mount CW, Monje M. Wrapped to Adapt: Experience-Dependent Myelination. Neuron. 2017 Aug 16;95(4):743-756. PubMed.
- Gibson EM, Nagaraja S, Ocampo A, Tam LT, Wood LS, Pallegar PN, Greene JJ, Geraghty AC, Goldstein AK, Ni L, Woo PJ, Barres BA, Liddelow S, Vogel H, Monje M. 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.
- Ng T, Teo SM, Yeo HL, Shwe M, Gan YX, Cheung YT, Foo KM, Cham MT, Lee JA, Tan YP, Fan G, Yong WS, Preetha M, Loh WJ, Koo SL, Jain A, Lee GE, Wong M, Dent R, Yap YS, Ng R, Khor CC, Ho HK, Chan A. Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer. Neuro Oncol. 2016 Feb;18(2):244-51. Epub 2015 Aug 19 PubMed.
- Nasrabady SE, Rizvi B, Goldman JE, Brickman AM. White matter changes in Alzheimer's disease: a focus on myelin and oligodendrocytes. Acta Neuropathol Commun. 2018 Mar 2;6(1):22. PubMed.
- Acharya MM, Green KN, Allen BD, Najafi AR, Syage A, Minasyan H, Le MT, Kawashita T, Giedzinski E, Parihar VK, West BL, Baulch JE, Limoli CL. Elimination of microglia improves cognitive function following cranial irradiation. Sci Rep. 2016 Aug 12;6:31545. PubMed.
- Miron VE. Microglia-driven regulation of oligodendrocyte lineage cells, myelination, and remyelination. J Leukoc Biol. 2017 May;101(5):1103-1108. Epub 2017 Mar 1 PubMed.
- Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, West BL, Green KN. Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. Brain. 2016 Apr;139(Pt 4):1265-81. Epub 2016 Feb 26 PubMed.
- Geraghty AC, Gibson EM, Ghanem RA, Greene JJ, Ocampo A, Goldstein AK, Ni L, Yang T, Marton RM, Paşca SP, Greenberg ME, Longo FM, Monje M. Loss of Adaptive Myelination Contributes to Methotrexate Chemotherapy-Related Cognitive Impairment. Neuron. 2019 May 10; PubMed.