Microglia regulate hippocampal neurogenesis during chronic neurodegeneration

Lucia, Chiara de; Rinchon, Adeline; Olmos-Alonso, Adrián; Riecken, Kristoffer; Fehse, Boris; Boche, Delphine; Perry, V. Hugh; Gómez-Nicola, Diego

doi:10.1016/j.bbi.2015.11.001

Cited by 100 publications

(89 citation statements)

References 53 publications

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“…We found a significant reduction in the expression of PU.1 and IRF8 in aging brains and a non-significant trend toward a reduction in relevant genes like CSF1 , CSF1R , C/EBPα , CD34 , or RUNX1 (Figure S3). To further address the significance of the CSF1R pathway in controlling microglial turnover, we administered young mice a diet containing GW2580, a specific CSF1R inhibitor previously shown to cause blockade of microglial proliferation, but not microglia survival (Gómez-Nicola et al., 2013, Uitdehaag et al., 2011, De Lucia et al., 2016, Olmos-Alonso et al., 2016), in contrast to the microglia-depleting effects caused by the CSF1R inhibitor PLX3397 (Elmore et al., 2014). Treatment with GW2580 for 3 months decreased the total number of microglial cells (PU.1 + ) by 17% (Figures 3F and 3G), supporting the relevance of the CSF1R pathway in controlling the homeostatic maintenance of microglial turnover.…”

Section: Resultsmentioning

confidence: 99%

Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain

et al. 2017

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SummaryMicroglia play key roles in brain development, homeostasis, and function, and it is widely assumed that the adult population is long lived and maintained by self-renewal. However, the precise temporal and spatial dynamics of the microglial population are unknown. We show in mice and humans that the turnover of microglia is remarkably fast, allowing the whole population to be renewed several times during a lifetime. The number of microglial cells remains steady from late postnatal stages until aging and is maintained by the spatial and temporal coupling of proliferation and apoptosis, as shown by pulse-chase studies, chronic in vivo imaging of microglia, and the use of mouse models of dysregulated apoptosis. Our results reveal that the microglial population is constantly and rapidly remodeled, expanding our understanding of its role in the maintenance of brain homeostasis.

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Section: Resultsmentioning

confidence: 99%

Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain

et al. 2017

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“…The CSF1R is primarily expressed on central nervous system microglial cells (De Lucia et al 2015) (Rademakers et al 2012), and it is reasonable to consider whether it may have mediated at least some of the inflammatory changes we observed. CSF1R is activated by the binding of CSF1, in the presence of or alternatively by IL-34, and is required for microglial viability.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Mitochondria and Mitochondrial Components Act as Damage-Associated Molecular Pattern Molecules in the Mouse Brain

Wilkins

Koppel

Weidling

et al. 2016

J Neuroimmune Pharmacol

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Mitochondria and mitochondrial debris are found in the brain’s extracellular space, and extracellular mitochondrial components can act as damage associated molecular pattern (DAMP) molecules. To characterize the effects of potential mitochondrial DAMP molecules on neuroinflammation, we injected either isolated mitochondria or mitochondrial DNA (mtDNA) into hippocampi of C57BL/6 mice and seven days later measured markers of inflammation. Brains injected with whole mitochondria showed increased Tnfα and decreased Trem2 mRNA, increased GFAP protein, and increased NFκB phosphorylation. Some of these effects were also observed in brains injected with mtDNA (decreased Trem2 mRNA, increased GFAP protein, and increased NFκB phosphorylation), and mtDNA injection also caused several unique changes including increased CSF1R protein and AKT phosphorylation. To further establish the potential relevance of this response to Alzheimer’s disease (AD), a brain disorder characterized by neurodegeneration, mitochondrial dysfunction, and neuroinflammation we also measured App mRNA, APP protein, and Aβ1-42 levels. We found mitochondria (but not mtDNA) injections increased these parameters. Our data show that in the mouse brain extracellular mitochondria and its components can induce neuroinflammation, extracellular mtDNA or mtDNA-associated proteins can contribute to this effect, and mitochondria derived-DAMP molecules can influence AD-associated biomarkers.

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“…Microglia are one of the major components of NPC niche and regulate neurogenesis in adult hippocampus (Gemma and Bachstetter, 2013; De Lucia et al, 2016). In the physiological conditions, surveillance microglia secrete trophic factors, such as the Insulin-like growth factor and Brain-derived neurotrophic factor, both of which are essential to neurogenesis (Lazarini et al, 2012; Matsuda et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Neurogenesis-Promoting Natural Product α-Asarone Modulates Morphological Dynamics of Activated Microglia

Cai

Mao

et al. 2016

Front. Cell. Neurosci.

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α-Asarone is an active constituent of Acori Tatarinowii, one of the widely used traditional Chinese Medicine to treat cognitive defect, and recently is shown to promote neurogenesis. Here, we demonstrated that low level (3 μM) of α-asarone attenuated LPS-induced BV2 cell bipolar elongated morphological change, with no significant effect on the LPS-induced pro-inflammatory cytokine expressions. In addition, time-lapse analysis also revealed that α-asarone modulated LPS-induced BV2 morphological dynamics. Consistently a significant reduction in the LPS-induced Monocyte Chemoattractant Protein (MCP-1) mRNA and protein levels was also detected along with the morphological change. Mechanistic study showed that the attenuation effect to the LPS-resulted morphological modulation was also detected in the presence of MCP-1 antibodies or a CCR2 antagonist. This result has also been confirmed in primary cultured microglia. The in vivo investigation provided further evidence that α-asarone reduced the proportion of activated microglia, and reduced microglial tip number and maintained the velocity. Our study thus reveals α-asarone effectively modulates microglial morphological dynamics, and implies this effect of α-asarone may functionally relate to its influence on neurogenesis.

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Microglia regulate hippocampal neurogenesis during chronic neurodegeneration

Abstract: HighlightsMicroglia are proneurogenic in a model of prion disease.Blocking the expansion of microglia prevents the aberrant differentiation of newborn neurons.TGFβ dominates the proneurogenic actions of microglia during chronic neurodegeneration.

Cited by 100 publications

References 53 publications

Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain

Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain

Extracellular Mitochondria and Mitochondrial Components Act as Damage-Associated Molecular Pattern Molecules in the Mouse Brain

Neurogenesis-Promoting Natural Product α-Asarone Modulates Morphological Dynamics of Activated Microglia

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