Microglia and CD206+ border-associated mouse macrophages maintain their embryonic origin during Alzheimer’s disease

  1. Xiaoting Wu
  2. Takashi Saito
  3. Takaomi C Saido
  4. Anna M Barron
  5. Christiane Ruedl

  • Curated by eLife

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    Evaluation Summary:

    This study by Wu et al., examined in a mouse model of Alzheimer how the lifespan and kinetics of both border-associated myeloid cells and microglia are affected. Taken together, these data provide evidence on the replenishment of CNS-associated myeloid cells under both steady-state and pathology.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Abstract

Brain microglia and border-associated macrophages (BAMs) display distinct spatial, developmental, and phenotypic features. Although at steady state, the origins of distinct brain macrophages are well-documented, the dynamics of their replenishment in neurodegenerative disorders remain elusive, particularly for activated CD11c + microglia and BAMs. In this study, we conducted a comprehensive fate-mapping analysis of murine microglia and BAMs and their turnover kinetics during Alzheimer’s disease (AD) progression. We used a novel inducible AD mouse model to investigate the contribution of bone marrow (BM) cells to the pool of fetal-derived brain macrophages during the development of AD. We demonstrated that microglia remain a remarkably stable embryonic-derived population even during the progression of AD pathology, indicating that neither parenchymal macrophage subpopulation originates from, nor is replenished by, BM-derived cells. At the border-associated brain regions, bona fide CD206 + BAMs are minimally replaced by BM-derived cells, and their turnover rates are not accelerated by AD. In contrast, all other myeloid cells are swiftly replenished by BM progenitors. This information further elucidates the turnover kinetics of these cells not only at steady state, but also in neurodegenerative diseases, which is crucial for identifying potential novel therapeutic targets.

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  1. Version published to 10.7554/elife.71879 on eLife
  2. eLife

    Evaluation Summary:

    This study by Wu et al., examined in a mouse model of Alzheimer how the lifespan and kinetics of both border-associated myeloid cells and microglia are affected. Taken together, these data provide evidence on the replenishment of CNS-associated myeloid cells under both steady-state and pathology.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

  3. eLife

    Reviewer #1 (Public Review):

    Wu et al. have focused on the question whether amyloid pathology could affect the turnover kinetics of both border-associated myeloid cells and CNS microglia. In order to rule out the effect from protein over-expression in rapid amyloid models, the authors utilized an AppNL-G-F knock-in (APP-KI) mouse model. Consistent with previous studies, they observed an increase of CD11c+ microglia (referred as DAM in this study) in the APP-KI mice. They also observed an increase of CD206+ BAMs associated with aging and AD pathology. Further lineage tracing with KitMerCreMer/R26YFP and KitMerCreMer/R26YFP/APP-KI mice confirmed that microglia (both CD11c- and CD11c+) in brain parenchyma retained the yolk sac origins regardless their activation state. Both CD11c- and CD11c+ microglia were not infiltrated by BM-derived myeloid cells in 10 month-old WT and APP-KI. On the other hand, other myeloid cells such as monocytes and MdCs were rapidly replaced within 2 months. Interestingly, border-associated myeloid cells (BAMs) at meningeal borders (including dura matter, subdural meninges and choroid plexus) showed significantly low turnover rate throughout whole life. Overall, these results provide vital information on the kinetics of replenishment of CNS-associated myeloid cells including BAMs and microglia under both normal and the neurodegenerative conditions.

  4. eLife

    Reviewer #2 (Public Review):

    Here, Wu and colleagues used an established Alzheimer mouse model in combination with a fate map approach to directly investigate potential residual contributions of peripheral hematopoiesis / monocytes to the microglia and BAM compartments. under AD pathology. Using a comprehensive flow cytometry-based analysis, the authors show that labelled cells contribute to a number of other myeloid populations, but neither microglia nor BAM receive significant peripheral input. This includes 'disease-associated' activated microglia that the authors define as P2RY12lo CD11c+ cells.

    This is in general a well-performed short report, addressing an important and timely topic. As mentioned by the authors, Wang et al (2016) showed in a seminal study that macrophages associated with Abeta plaques are bona fide microglia, and not HSC derived, as also discussed in (PMID: 28553330). The authors extend this finding by an analysis at higher resolution and including BAM, but novelty and conceptual advance are somewhat limited.

  5. eLife

    Reviewer #3 (Public Review):

    In the current manuscript, the authors analyzed the contribution of bone marrow-derived precursors to the pool of disease-associated microglia (DAMs) in a model of Alzheimer's disease (AD).

    Using flow cytometry, they first analyzed the different myeloid cells in the parenchyma and CNS border regions including dura mater, subdural meninges and choroid plexus. They demonstrate that also in the APP-KI (AppNL-G-F) AD mouse model, DAMs were detected while infiltrating myeloid cells were not increased in any of the regions in comparison to age-matched controls.

    To assess the origin of DAMs and BAMs, they used KitMerCreMerR26YFP mice crossed to APP-KI mice, which were treated with tamoxifen at different ages and analyzed at 10 months of age.

    Their results showed that DAMs and also BAMs were minimally labeled in these mice, demonstrating that they are not derived from labeled precursors.

    It is a nicely designed and performed study with clear data demonstrating that DAMs do not originate from circulating monocytes but are derived from homeostatic microglia.

    The authors demonstrate that also BAMs are mostly not replaced by monocytes. However, while they have analyzed BAMs in the meninges including the dura mater and pia mater and also in the choroid plexus, they have not mentioned or analyzed perivascular macrophages residing in the perivascular space around the parenchymal vasculature.

  6. Version published to 10.1101/2021.07.05.451201v1 on bioRxiv