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 microglia necroptosis and repopulation. Nat Neurosci. 2019 Jul;22(7):1046-1052. Epub 2019 Jun 10 PubMed.

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  1. What we’ve learned
    In this elegant study, Lloyd et al. show that a large number of pro-inflammatory microglia during acute demyelination undergo cell death in the form of necroptosis to give way to repopulating residual microglia with pro-remyelinating properties. Conversely, inhibiting microglial necroptosis and thereby clamping microglia in a pro-inflammatory state hindered effective remyelination. With this work, the team of Veronique Miron solves the long-standing mystery regarding the fate of the microglia population that becomes acutely activated during demyelination.

    While experimental microglia depletion has been shown to be beneficial in a variety of brain diseases, this work identifies a naturally occurring form of beneficial microglia, via depletion, which seems to be a very efficient mode of silencing inflammatory microglia gene signatures in vivo. It is tempting to speculate that this is especially true for the highly active microglia digesting myelin that probably have exceeded their lifetime capacity for phagocytosis. This work certainly provokes thought about how this natural form of microglial depletion can be boosted experimentally to further stimulate remyelination. In this context, it would have been interesting to show if the process of natural depletion is dysregulated in chronic active MS lesions. Likewise, it must be clear that the therapeutic window for such an intervention is small: The coordination of depleting pro-inflammatory and increasing pro-regenerative microglia needs to be tightly controlled in order to prevent premature remyelination in a pro-inflammatory environment—a remyelination that 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). White-matter damage in general, however, can be detected earlier than overt plaque pathology (e.g Agosta et al., 2011). Recently, two high-profile single-cell/nuclei transcriptomic studies in patients consistently identified myelination-related processes to be perturbed in AD (Mathys et al., 2019; Del-Aquila et al., 2019). With this, oligodendrocytes (which are yet the "forgotten players" in the context of AD) might quickly move into focus—and with them remyelinating therapies. Microglia depletion has been already suggested as potential therapeutic intervention in AD as it was shown to combat cognitive decline and neurodegeneration in aged and AD mice (Spangenberg et al., 2016; Elmore et al., 2018) and if applied at pre-plaque stages even Aβ plaque deposition (Sosna et al., 2018). 

    In this context, the study by Lloyd et al. contributes to our understanding of how microglial responses are tuned by depletion to enable efficient remyelination. When finding the correct time window (a caveat mentioned above) to eliminate pro-inflammatory microglia cells, experimental microglia depletion might be all the more attractive as a therapeutic intervention in AD, benefiting both remyelination and neuroprotection. Intriguingly, comparison of the post-demyelination microglial gene signature with the disease-associated microglia (DAM) gene signature (Karen-Shaul et al., 2017) revealed that DAMs are more similar to pro-regenerative than to demyelinating pro-inflammatory microglia. This finding awaits single-cell transcriptomic proof. Nevertheless, this would suggest that DAMs partly show a myelination-boosting gene signature and it is tempting to speculate that the switch to this pro-remyelinating microglia comes too early in AD and remyelination is therefore somewhat inefficient.

    Altogether, we foresee extensive research on the role of demyelination in AD and the evaluation of pro-remyelinating agents to combat AD-related demyelination in the near future. With the prominent and well-studied role of microglia in AD, this study by Lloyd et al. outlines a potential direction of this research very worth pursuing, namely the interplay of microglia states and remyelination. Again, we congratulate the authors for this excellent paper. 

    References:

    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.

    Agosta F, Pievani M, Sala S, Geroldi C, Galluzzi S, Frisoni GB, Filippi M. White matter damage in Alzheimer 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 transcriptomic analysis of Alzheimer's disease. Nature. 2019 Jun;570(7761):332-337. Epub 2019 May 1 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-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain. Alzheimers Res Ther. 2019 Aug 9;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(Pt 4):1265-81. Epub 2016 Feb 26 PubMed.

    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 the aged brain reverses cognitive, synaptic, and neuronal deficits in mice. Aging Cell. 2018 Dec;17(6):e12832. Epub 2018 Oct 2 PubMed.

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

    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.

    View all comments by Stefan Berghoff

  2. A mechanism of microglia cell-state transition at different stages of injury

    Microglia change their state, including physical or biochemical changes, to adapt to specific brain environments. Until recently these changes have been difficult to characterize, and were mostly grouped together using the term “activation.” It is becoming increasingly apparent that microglia assume many diverse states in the healthy (Hammond et al., 2019; Li et al., 2019) and diseased brain (Keren-Shaul et al., 2017; O’Koren et al., 2019; Mathys et al., 2017; Hammond et al., 2019), raising the important question of whether and how microglia transition between different cell states and the roles of each state/subpopulation in the brain.

    Dr. Miron’s previous work showed that over the course of demyelinating injury, microglia transition from an inflammatory to regenerative state, a change that is 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 microglia states to understand how this transition is regulated. Surprisingly, the authors show that the microglia do not transition between the two states, but rather the inflammatory microglia die by necroptosis to clear the way for the pro-regenerative subpopulation.

    These findings are important for several reasons: 1.) The ability of microglia to shift between inflammatory and regenerative activation states in disease could be limited. 2.) Once microglia become activated, it might be difficult for them to transition back to a resting state without dying. In AD, it is still unclear whether microglia occupy the different states identified in this study, particularly the inflammatory subpopulation that dies by necroptosis. The most well-known state, disease-associated microglia (DAM) (Keren-Shaul et al., 2017) associate with amyloid plaques and have a distinct profile that aligns partly with the activated microglia profiles found in the demyelination model used in this study but largely lacks the interferon signature found in the pro-regenerative microglia (see comparison in Hammond et al., 2019). Direct comparisons between several models of neurodegeneration will be needed to tease apart these differences.

    In AD it has been difficult to determine how and when microglia become activated and whether they occupy unique states at different stages of disease, as found in this study. Most AD mouse models are slow progressing and pathology accumulates at varying rates in different brain regions, making it difficult to address this question. However, an inducible model of neurodegeneration showed that following neuron death microglia occupy several distinct states similar to those found in the demyelination model (Mathys et al., 2017). Therefore, it is possible that microglia necroptosis also plays a role in AD, but this will need to be examined in greater detail.

    The development of new tools to track and manipulate resident microglia in the brain is needed to understand how and when microglia become “activated,” change state, and tailor their responses to specific disease conditions. This study provides an important leap forward in our understanding of microglia biology and functional states that could be broadly relevant to Alzheimer’s and other diseases.

    References:

    Mathys H, Adaikkan C, Gao F, Young JZ, Manet E, Hemberg M, De Jager PL, Ransohoff RM, Regev A, Tsai LH. Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution. Cell Rep. 2017 Oct 10;21(2):366-380. PubMed.

    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 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 the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. Immunity. 2019 Jan 15;50(1):253-271.e6. Epub 2018 Nov 21 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 Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing. Neuron. 2019 Jan 16;101(2):207-223.e10. Epub 2018 Dec 31 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 2013 Jul 21 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 Distinct in Different Anatomical Locations during Retinal Homeostasis and Degeneration. Immunity. 2019 Mar 19;50(3):723-737.e7. Epub 2019 Mar 5 PubMed.

    View all comments by Timothy Hammond View all comments by Beth Stevens

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