The role of P2Y12 in the kinetics of microglial self-renewal and maturation in the adult visual cortex in vivo

Mendes, Monique; Le, Linh; Atlas, Jason; Ladrón-de-Guevara, Antonio; Matei, Evelyn; Lamantia, Cassandra E.; McCall, Matthew N.; Majewska, Ania K.

doi:10.7554/elife.61173

Cited by 24 publications

(25 citation statements)

References 55 publications

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“…During depletion, surviving microglia are seen scattered throughout the brain (Figure 1A-B, C) and subsequent withdrawal of the inhibitor results in rapid and spatially homogenous microglial repopulation within 3d, with cells exceeding control numbers by 7d (Figure 1C, E). Recent studies show that repopulation is dependent on the local proliferation and clonal expansion of surviving microglia 24,26,27,[31][32][33] ; thus, we refer to this type of repopulation as global microglial (GLOBAL) repopulation.…”

Section: Cns Repopulationmentioning

confidence: 99%

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

Hohsfield

Najafi

Ghorbanian³

et al. 2021

eLife

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Microglia, the brain's resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using a prolonged colony-stimulating factor 1 receptor inhibitor (CSF1Ri) approach, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from the subventricular zone and associated white matter areas. Following CSF1Ri, these amoeboid cells migrate radially and tangentially in a dynamic wave filling the brain in a distinct pattern, to replace the microglial-depleted brain. These repopulating cells are enriched in disease-associated microglia genes and exhibit similar phenotypic and transcriptional profiles to white matter-associated microglia. Our findings shed light on the overlapping and distinct functional complexity and diversity of myeloid cells of the CNS and provide new insight into repopulating microglia function and dynamics in the mouse brain.

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Section: Cns Repopulationmentioning

confidence: 99%

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

Hohsfield

Najafi

Ghorbanian³

et al. 2021

eLife

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“…In this present study, we investigated the impact of pharmacologically induced microglial renewal on pathology, microglial activation, and gene expression using both the 3xTg and APP/PS1 mouse models of Alzheimer’s disease. Previous work from our laboratory and others demonstrated that adult microglia are capable of rapid self-renewal following depletion [ 28 , 47 ]. These new-born microglia are thought to be “rejuvenated” and beneficial in the context of disease settings such as toxin-induced acute neuronal lesion as well as normal aging [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Adult microglia have a remarkable capacity to selfrenew, and after depletion, repopulate their niche completely within 1 week, acquiring their normal densities, spacing, and morphological characteristics [25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Repopulated microglia induce expression of Cxcl13 with differential changes in Tau phosphorylation but do not impact amyloid pathology

Karaahmet

Mendes

et al. 2022

J Neuroinflammation

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Background Adult microglia rely on self-renewal through division to repopulate and sustain their numbers. However, with aging, microglia display morphological and transcriptional changes that reflect a heightened state of neuroinflammation. This state threatens aging neurons and other cells and can influence the progression of Alzheimer’s disease (AD). In this study, we sought to determine whether renewing microglia through a forced partial depletion/repopulation method could attenuate AD pathology in the 3xTg and APP/PS1 mouse models. Methods We pharmacologically depleted the microglia of two cohorts of 21- to 22-month-old 3xTg mice and one cohort of 14-month-old APP/PS1 mice using PLX5622 formulated in chow for 2 weeks. Following depletion, we returned the mice to standard chow diet for 1 month to allow microglial repopulation. We assessed the effect of depletion and repopulation on AD pathology, microglial gene expression, and surface levels of homeostatic markers on microglia using immunohistochemistry, single-cell RNAseq and flow cytometry. Results Although we did not identify a significant impact of microglial repopulation on amyloid pathology in either of the AD models, we observed differential changes in phosphorylated-Tau epitopes after repopulation in the 3xTg mice. We provide evidence that repopulated microglia in the hippocampal formation exhibited changes in the levels of homeostatic microglial markers. Lastly, we identified novel subpopulations of microglia by performing single-cell RNAseq analysis on CD45int/+ cells from hippocampi of control and repopulated 3xTg mice. In particular, one subpopulation induced after repopulation is characterized by heightened expression of Cxcl13. Conclusion Overall, we found that depleting and repopulating microglia causes overexpression of microglial Cxcl13 with disparate effects on Tau and amyloid pathologies.

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“…It would be of great interest to determine specific markers which allow the precise identification of highly neurotoxic and/or degenerated plaque-associated microglia, in order to specifically deplete them. Microglial proliferation which repopulate the depleted niche rapidly acquire mature characteristics [ 58 , 101 ] and may counteract AD pathology by better containing amyloid deposits and diminishing pathological phagocytosis of synapses, then contributing to the amelioration of AD cognitive decline.…”

Section: Do Microglia Refresh or Poison Ad Progression?mentioning

confidence: 99%

Should We Open Fire on Microglia? Depletion Models as Tools to Elucidate Microglial Role in Health and Alzheimer’s Disease

Romero‐Molina

Navarro

Jiménez

et al. 2021

IJMS

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Microglia play a critical role in both homeostasis and disease, displaying a wide variety in terms of density, functional markers and transcriptomic profiles along the different brain regions as well as under injury or pathological conditions, such as Alzheimer’s disease (AD). The generation of reliable models to study into a dysfunctional microglia context could provide new knowledge towards the contribution of these cells in AD. In this work, we included an overview of different microglial depletion approaches. We also reported unpublished data from our genetic microglial depletion model, Cx3cr1CreER/Csf1rflx/flx, in which we temporally controlled microglia depletion by either intraperitoneal (acute model) or oral (chronic model) tamoxifen administration. Our results reported a clear microglial repopulation, then pointing out that our model would mimic a context of microglial replacement instead of microglial dysfunction. Next, we evaluated the origin and pattern of microglial repopulation. Additionally, we also reviewed previous works assessing the effects of microglial depletion in the progression of Aβ and Tau pathologies, where controversial data are found, probably due to the heterogeneous and time-varying microglial phenotypes observed in AD. Despite that, microglial depletion represents a promising tool to assess microglial role in AD and design therapeutic strategies.

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The role of P2Y12 in the kinetics of microglial self-renewal and maturation in the adult visual cortex in vivo

Cited by 24 publications

References 55 publications

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

Repopulated microglia induce expression of Cxcl13 with differential changes in Tau phosphorylation but do not impact amyloid pathology

Should We Open Fire on Microglia? Depletion Models as Tools to Elucidate Microglial Role in Health and Alzheimer’s Disease

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