Lloyd AF, Davies CL, Holloway RK, Labrak Y, Ireland G, Carradori D, Dillenburg A, Borger E, Soong D, Richardson JC, Kuhlmann T, Williams A, Pollard JW, des Rieux A, Priller J, Miron VE.Central nervous system regeneration is driven by microglial necroptosis and repopulation.Nat Neurosci. 2019 Jul;22(7):1046-1052. Epub 10 June 2019 PubMed.

PleaseRegistrationrecommend the paper.

    • Constanze Depp
      Max Planck Institute for Experimental Medicine
    • Stefan Berghof
      Max Planck Institute for Experimental Medicine
    • Posted:
    • News: Dead microglia pave the way for myelin regeneration

    What we learned
    In this elegant study, Lloyd et al. show that large numbers of pro-inflammatory microglia undergo cell death in the form of necroptosis during acute demyelination to give way to repopulation of residual microglia with pro-remyelinating properties. Conversely, inhibition of microglial necroptosis, and thereby pinching the microglia into a pro-inflammatory state, prevented effective remyelination. With this work, Veronique Miron's team solves the long-standing mystery of the fate of the microglial population that is acutely activated during demyelination.

    While experimental microglial depletion has been shown to be beneficial in a variety of brain diseases, this work identifies a naturally occurring form of beneficial microglia through depletion, which appears to be a very efficient method to silence inflammatory microglial gene signatures in vivo . It is tempting to speculate that this is particularly true of the highly active microglia that digest myelin, which have likely exceeded their lifetime capacity for phagocytosis. This work certainly gives food for thought as to how this natural form of microglial depletion can be experimentally enhanced to further stimulate remyelination. In this context, it would have been interesting to show whether the natural degradation process is dysregulated in chronically active MS lesions. Likewise, it must be clear that the therapeutic window for such an intervention is small: the coordination of decreasing proinflammatory and increasing proregenerative microglia must be tightly controlled to prevent premature remyelination in a proinflammatory environment—myelination—is doomed to fail.

    What this means for AD-related demyelination
    In AD, demyelination has been shown to occur focally at Aβ plaques (Behrendt et al., 2013). However, white matter damage in general can be detected earlier than overt plaque pathology (e.g.,Augusta et al., 2011). Recently, two high-profile single cell/nucleus transcriptomic studies in patients consistently identified myelinization-related processes that are disrupted in AD (Mathis et al., 2019;Del-Aquila et al., 2019). This could quickly bring oligodendrocytes (so far the “forgotten actors” in connection with AD) into focus – and with them remyelinating therapies. Microglial depletion has previously been suggested as a potential therapeutic intervention in AD, as it has been shown to combat cognitive decline and neurodegeneration in aged and AD mice (Spangenberg et al., 2016;Elmoreet al., 2018) and even Aβ plaque deposition when applied in pre-plaque stages (Sosna et al., 2018).

    The study by Lloyd et al. contributes to our understanding of how microglial responses are tuned by depletion to allow efficient remyelination. If the right time window (a caveat noted above) is found to eliminate pro-inflammatory microglial cells, experimental microglial depletion could be all the more attractive as a therapeutic intervention in AD, benefiting both remyelination and neuroprotection. Interestingly, a comparison of the microglia gene signature after demyelination with the disease-associated microglia (DAM) gene signature (Karen-Shaul et al., 2017) showed that DAMs resemble proregenerative rather than demyelinating proinflammatory microglia. This finding awaits transcriptomic single cell detection. Nonetheless, this would suggest that DAMs partially carry a myelination-promoting gene signature, and it is tempting to speculate that the switch to these pro-remyelinating microglia in AD occurs too early and that remyelination is therefore somewhat inefficient.

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    Overall, we expect extensive research into the role of demyelination in AD and the evaluation of pro-remyelination agents to combat AD-related demyelination in the near future. Given the prominent and well-studied role of microglia in AD, this study by Lloyd et al. outlines a potential direction of this research worth pursuing, namely the interplay of microglial states and remyelination. Congratulations again to the authors for this excellent work.


    Behrendt G, Baer K, Buffo A, Curtis MA, Faull RL, Rees MI, Götz M, Dimou L.Dynamic changes in myelin aberrations and oligodendrocyte generation in chronic amyloidosis in mice and men.Glia. 2013 Feb;61(2):273-86. PubMed.

    F. Agosta, M. Pievani, S. Sala, C. Geroldi, S. Galluzzi, GB Frisoni, M. Filippi.White matter damage in Alzheimer's disease and its relationship to gray matter atrophy.Radiology. 2011 Mar;258(3):853-63. PubMed.

    Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, Menon M, He L, Abdurrob F, Jiang X, Martorell AJ, Ransohoff RM, Hafler BP, Bennett DA, Kellis M, Tsai LH..Single cell transcriptome analysis of Alzheimer's disease.Nature. 2019 Jun;570(7761):332-337. Epub 1. Mai 2019 PubMed.

    Del-Aguila JL, Li Z, Dube U, Mihindukulasuriya KA, Budde JP, Fernandez MV, Ibanez L, Bradley J, Wang F, Bergmann K, Davenport R, Morris JC, Holtzman DM, Perrin RJ, Benitez BA, Dougherty J, Cruchaga C, Harari O.A single core RNA sequencing study of Mendelian and sporadic AD in the human brain.Alzheimers Res Ther. 9. August 2019;11(1):71. 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(Part 4):1265-81. Epub 2016 February 26th PubMed.

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    Elmore MR, Hohsfield LA, Kramár EA, Soreq L, Lee RJ, Pham ST, Najafi AR, Spangenberg EE, Wood MA, West BL, Green KN.Replacement of microglia in aged brain reverses cognitive, synaptic and neuronal deficits in mice.aging cell. 2018 Dez;17(6):e12832. Epub 2018 2. Okt PubMed.

    Sosna J, Philipp S, Albay R 3., Reyes-Ruiz JM, Baglietto-Vargas D, LaFerla FM, Glabe CG.Long-term early administration of the CSF1R inhibitor PLX3397 clears microglia and reduces the accumulation of intraneuronal amyloid, neuritic plaque deposition, and prefibrillar oligomers in the 5XFAD mouse model of Alzheimer's disease.Mol Neurodegener. Mar 1, 2018;13(1):11. PubMed.

    H Keren-Shaul, A Spinrad, A Weiner, O Matcovitch-Nathan, R Dvir-Szternfeld, TK Ulland, E David, K Baruch, D Lara-Astaiso, B Toth, S Itzkovitz , M. Colonna , M. Schwartz , I. Amit.A unique type of microglia associated with limiting the development of Alzheimer's disease.cell. 2017 Jun 15;169(7):1276-1290.e17. Epub June 8, 2017 PubMed.

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    • Timotheus Hammond
      Boston Children's Hospital
    • Beth Stevens
      Children's Hospital
    • Posted:

    A mechanism of state transition of microglial cells in different stages of injury

    Microglia change state, including physical or biochemical changes, to adapt to specific brain environments. Until recently, these changes were difficult to characterize and were mostly grouped under the term "activation". It is becoming increasingly clear that microglia in healthy (Hammond et al., 2019;Liet al., 2019) and sick brain (Keren-Shaul et al., 2017;O'Koren et al., 2019;Mathis et al., 2017;Hammond et al., 2019), which raises the important question of whether and how microglia switch between different cell states and what role each state/subpopulation plays in the brain.

    The previous work of Dr. Miron showed that microglia transition from an inflammatory to a regenerative state during the course of demyelinating injury, a change required for normal tissue repair (Miron et al., 2013). In this study, Lloyd and colleagues use genomics, ex vivo explant assays, and in vivo manipulation of different microglial states to understand how this transition is regulated. Surprisingly, the authors show that the microglia do not switch between the two states, but instead the inflammatory microglia die by necroptosis to give way to the proregenerative subpopulation.

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    These results are important for several reasons: 1.) The ability of microglia to switch between inflammatory and regenerative activation states in disease may be impaired. 2.) Once microglia are activated, it can be difficult for them to return to a dormant state without dying. In AD, it is still unclear whether microglia adopt the various states identified in this study, particularly the inflammatory subpopulation that dies by necroptosis. The best-known condition, disease-associated microglia (DAM) (Keren-Shaul et al., 2017) associate with amyloid plaques and have a distinct profile that is partially consistent with the activated microglial profiles found in the demyelination model used in this study, but largely lacks the interferon signature found in the proregenerative microglia (see comparison inHammond et al., 2019). Direct comparisons between multiple models of neurodegeneration are needed to uncover these differences.

    In AD, it has been difficult to determine how and when microglia are activated and whether they adopt unique states at different disease states, as noted in this study. Most AD mouse models develop slowly and pathology accumulates at different rates in different brain regions, making this question difficult to answer. However, an inducible model of neurodegeneration showed that after neuron death, microglia adopt several distinct states that are similar to those found in the demyelination model (Mathis et al., 2017). Therefore, it is possible that microglial necroptosis also plays a role in AD, but this needs further investigation.

    The development of new tools to track and manipulate resident microglia in the brain is required to understand how and when microglia become "activated", change their state, and tailor their responses to specific disease states. This study represents an important advance in our understanding of microglial biology and functional states that may be important in Alzheimer's and other diseases.


    H. Mathys, C. Adaikkan, F. Gao, JZ Young, E. Manet, M. Hemberg, PL De Jager, RM Ransohoff, A. Regev, LH Tsai..Temporal tracking of microglial activation in neurodegeneration at single-cell resolution.Zellrep. 10. Oct. 2017;21(2):366-380. PubMed.

    H Keren-Shaul, A Spinrad, A Weiner, O Matcovitch-Nathan, R Dvir-Szternfeld, TK Ulland, E David, K Baruch, D Lara-Astaiso, B Toth, S Itzkovitz , M. Colonna , M. Schwartz , I. Amit.A unique type of microglia associated with limiting the development of Alzheimer's disease.cell. 2017 Jun 15;169(7):1276-1290.e17. Epub June 8, 2017 PubMed.

    Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, Walker AJ, Gergits F, Segel M, Nemesh J, Marsh SE, Saunders A, Macosko E, Ginhoux F, Chen J, Franklin RJ, Piao X, McCarroll SA, Stevens B.Single-cell RNA sequencing of microglia throughout mouse lifespan and in the injured brain reveals complex changes in cellular state.immunity. 15. Jan. 2019;50(1):253-271.e6. Epub 2018 21.11 PubMed.

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    [ PubMed ] Li Q, Cheng Z, Zhou L, Darmanis S, Neff NF, Okamoto J, Gulati G, Bennett ML, Sun LO, Clarke LE, Marschallinger J, Yu G, Quake SR, Wyss-Coray T, Barres BA.Developmental heterogeneity of microglia and myeloid brain cells revealed by deep single-cell RNA sequencing.Neuron. 2019-01-16;101(2):207-223.e10. Epub December 31, 2018 PubMed.

    Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJ, Ffrench-Constant C.M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination.Nat Neurosci. 2013 Sep;16(9):1211-1218. Epub 21. Juli 2013 PubMed.

    O'Koren EG, Yu C, Klingeborn M, Wong AY, Prigge CL, Mathew R, Kalnitsky J, Msallam RA, Silvin A, Kay JN, Bowes Rickman C, Arshavsky VY, Ginhoux F, Merad M, Saban DR.Microglial function is different at different anatomical sites during retinal homeostasis and degeneration.immunity. . . . 19 March 2019;50(3):723–737.e7. Epub 2019 Mar PubMed.

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