Microglia are continuously activated in the circumventricular organs of mouse brain

Takagi, Shun; Furube, Eriko; Nakano, Yousuke; Morita, Mitsuhiro; Miyata, Seiji

doi:10.1016/j.jneuroim.2017.10.008

Cited by 43 publications

(47 citation statements)

References 81 publications

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“…M1 and M2 microglia express different marker proteins, iNOS and CD16/32 are mainly expressed in M1 microglia, and CD206, Arginase I, and Ym1 are expressed in M2 microglia (Takagi, Furube, Nakano, Morita, & Miyata, ; Tang & Le, ). Our previous study demonstrated that naringenin reduced Aβ plaques and improved memory function (Yang et al, ).…”

Section: Resultsmentioning

confidence: 99%

Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression

Yang

Kuboyama

Tohda

2019

Phytotherapy Research

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Two kinds of microglia are known, classical M1 and alternative M2 phenotypes. Amyloid β (Aβ), a critical cause of Alzheimer's disease (AD), promotes M1 microglial polarization, leading to neuroinflammation and neuronal death. M2 microglia play important roles in anti-inflammatory effects, Aβ clearance, and memory recovery in AD. Therefore, increasing of M2 microglia is expected to recover from AD. We previously found that naringenin, a blood-brain barrier penetrating compound, decreased Aβ deposits and recovers memory function in transgenic AD model mice. Naringenin reportedly showed anti-inflammatory properties. Here, we aim to investigate potential effects of naringenin on microglial polarization and to reveal the underlying mechanisms of Aβ reduction. Primary cultured cortical microglia were treated with Aβ 1-42 , following administration of naringenin. Naringenin remarkably promoted M2 microglia polarization and inhibited Aβ 1-42 -induced M1 microglia activation. Because microglia reportedly played a critical role in cerebral Aβ clearance through Aβ degradation enzymes after phagocytosis, we investigated the expression of Aβ degradation enzymes, such as neprilysin and insulin degradation enzyme. After naringenin treatment, these Aβ degradation enzymes were downregulated in M1 microglia and upregulated in M2 microglia. Taken together, our results showed that naringenin increased Aβ degradation enzymes in M2 microglia, probably leading to Aβ plaque reduction.

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Section: Resultsmentioning

confidence: 99%

Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression

Yang

Kuboyama

Tohda

2019

Phytotherapy Research

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“…Another recent study detecting the level of 14 C in genomic DNA of microglia isolated from the human brain showed that 28% of human microglia, with an average life-span of 4.2 years, were renewed every year and most of which continued to do so indefinitely [47]. Using a multicolor fluorescent mapping [30,31,33,34]; Lower in human cerebral GM than WM [39] High [30,31]; Lower in CA3 than CA1 [21] High in CVOs [49] Average [30,31] or high [32]; Higher in SNr than VTA [65] Low [30,31,33,34]; Higher in cerebellar nuclei and granular layers [30,40]; Less CD68+ & MHCII+ in human cerebellum [38,39] Low [136,137] Morphology (ramification) High [33,34] High [33,34] Amoeboid [30,49,52] Higher in SNr than VTA [65] Low [33,34] Average; Cell smaller in dorsal horn [138] Molecular expression CX3CR1…”

Section: Heterogeneity In Microglial Density Across Cns Regionsmentioning

confidence: 99%

“…Low Sirpa [136] Others (NF-κB, CD11b, MHCII, Tim3, etc.) Higher in human WM [66,75,76] Median [59,62,63,136] High [49] Median [59,62,63,136] Median [59,62,63,136] High [59,62,63,136] Cellular functions: Proliferation/replenish after ablation Both fast [42] Both fast [46,48] Both fast [44,45,104] Replenish fast [42] Fast [48] /replenish slower [42] Replenish fast [42] Protrusion toward ATP/ Phagocytosis/pruning Fast protrusion [52]/Low lysosome content in NAc [65] High surveillance [74,82] Slow protrusion [ [111,112] Hoxb8 − , [101]; Sensitive to CSF1 [113] but not IL-34 [111,112] Unknown system by crossing CX3CR1 creER mice with R26 Confetti reporter mice, Tay et al observed that microglia established a dense network with highly variable turnover rates in multiple brain regions, which challenges the concept of microglial longevity in a healthy brain [48]. They reported subtly (oneto-two cycles) more active cell division in hippocampal and cerebel...…”

Section: Heterogeneity In Microglial Density Across Cns Regionsmentioning

confidence: 99%

Microglial regional heterogeneity and its role in the brain

2019

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Microglia have been recently shown to manifest a very interesting phenotypical heterogeneity across different regions in the mammalian central nervous system (CNS). However, the underlying mechanism and functional meaning of this phenomenon are currently unclear. Baseline diversities of adult microglia in their cell number, cellular and subcellular structures, molecular signature as well as relevant functions have been discovered. But recent transcriptomic studies using bulk RNAseq and single-cell RNAseq have produced conflicting results on region-specific signatures of microglia. It is highly speculative whether such spatial heterogeneity contributes to varying sensitivities of individual microglia to the same physiological and pathological signals in different CNS regions, and hence underlie their functional relevance for CNS disease development. This review aims to thoroughly summarize up-to-date knowledge on this specific topic and provide some insights on the potential underlying mechanisms, starting from microgliogenesis. Understanding regional heterogeneity of microglia in the context of their diverse neighboring neurons and other glia may provide an important clue for future development of innovative therapies for neuropsychiatric disorders.

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“…Some studies based on comprehensive single cell RNA sequencing experiments have reported that microglia do not vary considerably in the whole brain (Keren‐Shaul et al, ; Matcovitch‐Natan et al, ). However, a recent study provides further novel evidence that CD11b + microglia in the circumventricular regions are actually maintained in the activated state even during physiological conditions (Takagi, Furube, Nakano, Morita, & Miyata, ). Microglia in this specific region not only display the amoeboid morphology rather than the ramified form, but also express high protein levels of activation markers in the healthy mouse brain (Takagi et al, ).…”

Section: Introductionmentioning

confidence: 99%

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Han

Zhu

Zhang

et al. 2018

Glia

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Microglia are prominent immune cells in the central nervous system (CNS) and are critical players in both neurological development and homeostasis, and in neurological diseases when dysfunctional. Our previous understanding of the phenotypes and functions of microglia has been greatly extended by a dearth of recent investigations. Distinct genetically defined subsets of microglia are now recognized to perform their own independent functions in specific conditions. The molecular profiling of single microglial cells indicates extensively heterogeneous reactions in different neurological disorders, resulting in multiple potentials for crosstalk with other kinds of CNS cells such as astrocytes and neurons. In settings of neurological diseases it could thus be prudent to establish effective cell‐based therapies by targeting entire microglial networks. Notably, activated microglial depletion through genetic targeting or pharmacological therapies within a suitable time window can stimulate replenishment of the CNS niche with new microglia. Additionally, enforced repopulation through provision of replacement cells also represents a potential means of exchanging dysfunctional with functional microglia. In each setting the newly repopulated microglia might have the potential to resolve ongoing neuroinflammation. In this review, we aim to summarize the most recent knowledge of microglia and to highlight microglial depletion and subsequent repopulation as a promising cell replacement therapy. Although glial cell replacement therapy is still in its infancy and future translational studies are still required, the approach is scientifically sound and provides new optimism for managing the neurotoxicity and neuroinflammation induced by activated microglia.

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Microglia are continuously activated in the circumventricular organs of mouse brain

Cited by 43 publications

References 81 publications

Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression

Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression

Microglial regional heterogeneity and its role in the brain

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

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