Réu P, Khosravi A, Bernard S, Mold JE, Salehpour M, Alkass K, Perl S, Tisdale J, Possnert G, Druid H, Frisén J. The Lifespan and Turnover of Microglia in the Human Brain. Cell Rep. 2017 Jul 25;20(4):779-784. PubMed.

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  1. Füger et al. use an inheritable tagging system to track individual microglia over prolonged periods of time. By imaging the same cells every two weeks, it is possible that several cycles of proliferation/death are missed, therefore leading to an underestimation of microglial turnover. This could explain the discrepancy of their findings with those reported by us and others, including Réu and colleagues, wherein the turnover rates suggested the microglial population renews several times in a lifetime (Babcock et al., 2013; Askew et al., 2017; Tay et al., 2017). It is also unclear how representative the tagged population is when compared to all microglia, as their sensitivity to tamoxifen-induced recombination could suggest a different phenotype. It will be useful to see similar studies replicated in the future, by using alternative methodological approaches.

    Füger et al.’s study of microglial turnover in a mouse model of AD-like pathology provides a useful replication of previously reported findings by our group and others (Olmos-Alonso et al., 2016) and puts microglial proliferation in the spotlight of AD pathology.

    In this sense, the study by Réu et al. is very useful and provides a human “reality check” to compare murine studies against. Although some method-dependent variability was documented in this paper, the authors provide solid evidence that the degree of microglial turnover in people is higher than thought before. This is of particular importance for humans, as our longer life expectancy makes the microglial population susceptible to multiple renewal cycles in a lifetime.

    An exciting follow-up of these and previous studies will be to understand how a constant remodeling of the microglial population impacts on the physiology of their surrounding cells, as in, for example, microglia’s recently discovered influence on synaptic activity.

    References:

    Babcock AA, Wirenfeldt M, Finsen B. Quantification of microglial proliferation and apoptosis by flow cytometry. Methods Mol Biol. 2013;1041:129-45. PubMed.

    Askew K, Li K, Olmos-Alonso A, Garcia-Moreno F, Liang Y, Richardson P, Tipton T, Chapman MA, Riecken K, Beccari S, Sierra A, Molnár Z, Cragg MS, Garaschuk O, Perry VH, Gomez-Nicola D. Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain. Cell Rep. 2017 Jan 10;18(2):391-405. PubMed.

    Tay TL, Mai D, Dautzenberg J, Fernández-Klett F, Lin G, Sagar, Datta M, Drougard A, Stempfl T, Ardura-Fabregat A, Staszewski O, Margineanu A, Sporbert A, Steinmetz LM, Pospisilik JA, Jung S, Priller J, Grün D, Ronneberger O, Prinz M. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat Neurosci. 2017 Jun;20(6):793-803. Epub 2017 Apr 17 PubMed.

    Olmos-Alonso A, Schetters ST, Sri S, Askew K, Mancuso R, Vargas-Caballero M, Holscher C, Perry VH, Gomez-Nicola D. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. Brain. 2016 Mar;139(Pt 3):891-907. Epub 2016 Jan 8 PubMed.

    View all comments by Diego Gómez-Nicola

  2. It is excellent to see that Füger et al. have succeeded with longitudinal live imaging of steady-state microglial network over a reasonably long period and with such good resolution. We attempted to do this with the Microfetti mouse (Tay et al., 2017), but the XFP signals were not sufficiently bright for standard two-photon microscopy to perform the analysis reliably. The long-term tracking of neocortical microglia in this new study reproduces our predictions that cortical microglia are more likely to survive the entire lifespan of a mouse than microglia in other brain regions. In contrast to the cortex, our lineage analyses also pointed to more rapid turnover of microglia in the hippocampus and cerebellum, which correlates to higher immune surveillance and bioenergetics reported for microglia residing in these compartments (Grabert et al., 2016). The observation that non-plaque-associated microglia proliferated threefold quicker in the AD mouse model than in wildtype mouse, coupled with Reu et al.’s evidence that about a third of human microglia turn over in a year, raises the question of whether high turnover is a sign of microglial exhaustion, or if it increases the susceptibility for disease. Or both.

    I am excited about how quickly the field is moving and that many groups are making significant contributions to the progress. In particular, I wonder how we can now reconcile the properties of the disease-associated microglia (DAM) published recently (Keren-Shaul et al., 2017) with the hypothesis of microglial recruitment to plaques proposed in the Füger study. Are these the same type of microglial cells? Does a subset of the non-plaque-associated microglia exclusively adopt a DAM signature and therefore move toward a plaque? If so, would this be a chance event, or are highly proliferative microglial cells more prone to becoming DAM? Would it be informative to perform long-term imaging of microglia of AD mouse models in a Trem2-/- or Tyrobp -/- background? Also, how do we interpret this hypothesis in relation to the data showing BrdU-labeled microglia surrounding a plaque, albeit it is not clear if the authors distinguished between plaque- and non-plaque-associated microglia in this study (Olmos-Alonso et al., 2016)? 

    References:

    Tay TL, Mai D, Dautzenberg J, Fernández-Klett F, Lin G, Sagar, Datta M, Drougard A, Stempfl T, Ardura-Fabregat A, Staszewski O, Margineanu A, Sporbert A, Steinmetz LM, Pospisilik JA, Jung S, Priller J, Grün D, Ronneberger O, Prinz M. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat Neurosci. 2017 Jun;20(6):793-803. Epub 2017 Apr 17 PubMed.

    Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK, Stevens MP, Freeman TC, Summers KM, McColl BW. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat Neurosci. 2016 Mar;19(3):504-16. Epub 2016 Jan 18 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.

    Olmos-Alonso A, Schetters ST, Sri S, Askew K, Mancuso R, Vargas-Caballero M, Holscher C, Perry VH, Gomez-Nicola D. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. Brain. 2016 Mar;139(Pt 3):891-907. Epub 2016 Jan 8 PubMed.

    View all comments by Tuan Leng Tay

  3. Although there were several attempts to determine the age and turnover of microglia in the past, this is what the field has been waiting for for a long time! Now, we know it: Mice are basically born not only with most, if not all, of their neurons and oligodendrocytes, but also with most of their microglia. At least in mice, microglia seem to survive through an entire life span! Of course, we must keep in mind that laboratory mice are kept under extremely artificial, super-clean conditions, which certainly will influence microglia survival tremendously and almost certainly reduce heterogeneity of microglial populations (see below).

    And, are we aging with an increasing set of "primed" microglia? Does this finding mean we may have long-lived populations of all microglia that have been primed for all types of pathological insults that once happened in our brain? And what happens when these microglia age? Do they lose their function, e.g., to fight neuropathology during the progression of AD? 

    The Jucker lab also showed that microglia proliferate in response to disease pathology. This finding leads to the important question of the fate of these cells. Do old cells divide "asymmetrically” and produce young "offspring”? All these questions will have an important influence on the current search for microglial modulating therapeutic strategies.

    Yes, we must keep in mind that in humans the situation may be slightly different, probably because we are challenged constantly by all types of pathological insults. The paper by Reu et al. shows that very nicely. They determined the lifespan and turnover of human microglia by the analysis of the integration of atmospheric 14C derived from nuclear bomb tests into genomic DNA. Their results in humans show some important differences to mice: Human microglia have an average age of 4.2 years and about 28 percent are replaced every year. Thus, most human microglia are indeed renewed throughout life and there is no evidence for very long-lived microglia as in mice. The questions, however, are the same. What is the state of the renewed microglia? Are they fully functional in a homeostatic state and fully capable of quickly responding to pathological insults?

    View all comments by Christian Haass

  4. Microglia are macrophages of the central nervous system (CNS) and as such belong the hematopoietic system that also includes, for example, B and T cells. What is special for microglia cells is that they seed the CNS very early during embryonic development and probably very little after birth. In other words, most evidence so far, almost all from studies with mice, show that these cells are maintained in the CNS through adulthood, but do not need a constant feed from the bone marrow, unlike other cells of the hematopoietic origin.

    This from Réu et al. reports interesting findings and provides a strong argument on the turnover rate of human microglia cells. The authors have shown that in humans, and not only in mice, microglia cells are renewed slowly from long-lived cells that are present in the CNS. The implications of this study are that unlike other hematopoietic cells, microglia are “old.” They originate from cells that reached the CNS in the embryonic stage and their progenitors are not fresh cells that come via the blood to the CNS. This means that the microglia age just like other cells of the CNS.

    View all comments by Ari Waisman

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