Emerging Roles for CSF-1 Receptor and its Ligands in the Nervous System

Chiţu, Violeta; Gökhan, Şölen; Nandi, Sayan; Mehler, Mark F.; Stanley, E. Richard

doi:10.1016/j.tins.2016.03.005

Cited by 280 publications

(250 citation statements)

References 109 publications

(196 reference statements)

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“…We point out that CSF1R inhibition also affects cells other than microglia, which may have contributed to the catatonic phenotype (45). Upon CSF1R inhibition, we saw not only a decline in CD3 + T cells that are attracted to the brain by the inflammatory milieu and may influence microglial behavior, but also a decrease in the GFAP + area as a measure of robust astrogliosis.…”

Section: Catatonia and Ihc Markers Of Brain Inflammation And Neurodegmentioning

confidence: 62%

Microglia ablation alleviates myelin-associated catatonic signs in mice

Jáňová

Arinrad

Balmuth

et al. 2017

Journal of Clinical Investigation

103

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Section: Catatonia and Ihc Markers Of Brain Inflammation And Neurodegmentioning

confidence: 62%

Microglia ablation alleviates myelin-associated catatonic signs in mice

Jáňová

Arinrad

Balmuth

et al. 2017

Journal of Clinical Investigation

103

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“…Furthermore, microglia play a relevant role in removing damaged neurons and neuronal components, such as aberrant synaptic terminals or demyelinated axons. In this sense, deficiencies in key genes for microglial survival and/or proliferation (such as CSF1R or TREM2) are associated with rare hereditary neurodegenerative diseases, such as adult-onset leukoencephalopathy with axonal spheroids or Nasu–Hakola disease (respectively) [6, 38, 39]. In both diseases, the microglial response and, more relevant, the microglial survival seem to be compromised.…”

Section: Discussionmentioning

confidence: 99%

Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration

et al. 2016

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The role of microglial cells in the development and progression of Alzheimer’s disease (AD) has not been elucidated. Here, we demonstrated the existence of a weak microglial response in human AD hippocampus which is in contrast to the massive microglial activation observed in APP-based models. Most importantly, microglial cells displayed a prominent degenerative profile (dentate gyrus > CA3 > CA1 > parahippocampal gyrus), including fragmented and dystrophic processes with spheroids, a reduced numerical density, and a significant decrease in the area of surveillance (“microglial domain”). Consequently, there was a substantial decline in the area covered by microglia which may compromise immune protection and, therefore, neuronal survival. In vitro experiments demonstrated that soluble fractions (extracellular/cytosolic) from AD hippocampi were toxic for microglial cells. This toxicity was abolished by AT8 and/or AT100 immunodepletion, validating that soluble phospho-tau was the toxic agent. These results were reproduced using soluble fractions from phospho-tau-positive Thy-tau22 hippocampi. Cultured microglial cells were not viable following phagocytosis of SH-SY5Y cells expressing soluble intracellular phospho-tau. Because the phagocytic capacity of microglial cells is highly induced by apoptotic signals in the affected neurons, we postulate that accumulation of intraneuronal soluble phospho-tau might trigger microglial degeneration in the AD hippocampus. This microglial vulnerability in AD pathology provides new insights into the immunological mechanisms underlying the disease progression and highlights the need to improve or develop new animal models, as the current models do not mimic the microglial pathology observed in the hippocampus of AD patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1630-5) contains supplementary material, which is available to authorized users.

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“…While IL34 regulates the development and maintenance of microglia in forebrain structures, M-CSF seems to control microglia populations in white matter areas, and, to a lesser extent, in the cortex and cerebellum (Kondo and Duncan, 2009; Nandi et al, 2012). Lastly, M-CSF and CSF-1R-deficient mice present brain abnormalities and die before adulthood (Ginhoux et al, 2010), whereas brains in mice deficient in IL34 are largely normal (Wang et al, 2012), suggesting that only M-CSF, through CSF-1R signaling, is responsible for overall brain development (Chitu et al, 2016). M-CSF is highly expressed in the yolk sac, and it may contribute to the expansion of microglial precursors, whereas IL34 does not control embryonic development of microglia (Ginhoux et al, 2010; Greter et al, 2012).…”

Section: The Endocytic Pathway In Phagocytic Cellsmentioning

confidence: 99%

The endocytic pathway in microglia during health, aging and Alzheimer’s disease

Solé-Domènech

Cruz

Capetillo-Zárate

et al. 2016

Ageing Research Reviews

106

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Microglia, the main phagocytes of the central nervous system (CNS), are involved in the surveillance and maintenance of nervous tissue. During normal tissue homeostasis, microglia migrate within the CNS, phagocytose dead cells and tissue debris, and modulate synapse pruning and spine formation via controlled phagocytosis. In the event of an invasion by a foreign body, microglia are able to phagocytose the invading pathogen and process it proteolytically for antigen presentation. Internalized substrates are incorporated and sorted within the endocytic pathway and thereafter transported via complex vesicular routes. When targeted for degradation, substrates are delivered to acidic late endosomes and lysosomes. In these, the enzymatic degradation relies on pH and enzyme content. Endocytosis, sorting, transport, compartment acidification and degradation are regulated by complex signaling mechanisms, and these may be altered during aging and pathology. In this review, we discuss the endocytic pathway in microglia, with insight into the mechanisms controlling lysosomal biogenesis and pH regulation. We also discuss microglial lysosome function associated with Alzheimer’s disease (AD) and the mechanisms of amyloid-beta (Aβ) internalization and degradation. Finally, we explore some therapies currently being investigated to treat AD and their effects on microglial response to Aβ, with insight in those involving enhancement of lysosomal function.

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Emerging Roles for CSF-1 Receptor and its Ligands in the Nervous System

Cited by 280 publications

References 109 publications

Microglia ablation alleviates myelin-associated catatonic signs in mice

Microglia ablation alleviates myelin-associated catatonic signs in mice

Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration

The endocytic pathway in microglia during health, aging and Alzheimer’s disease

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