Unique microglia recovery population revealed by single-cell RNAseq following neurodegeneration

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Abstract

Microglia are brain immune cells that constantly survey their environment to maintain homeostasis. Enhanced microglial reactivity and proliferation are typical hallmarks of neurodegenerative diseases. Whether specific disease-linked microglial subsets exist during the entire course of neurodegeneration, including the recovery phase, is currently unclear. Taking a single-cell RNA-sequencing approach in a susceptibility gene-free model of nerve injury, we identified a microglial subpopulation that upon acute neurodegeneration shares a conserved gene regulatory profile compared to previously reported chronic and destructive neurodegeneration transgenic mouse models. Our data also revealed rapid shifts in gene regulation that defined microglial subsets at peak and resolution of neurodegeneration. Finally, our discovery of a unique transient microglial subpopulation at the onset of recovery may provide novel targets for modulating microglia-mediated restoration of brain health.

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Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.

Bahareh Ajami, Jami Bennett, Charles Krieger … (2007)

Microgliosis is a common response to multiple types of damage in the CNS. However, the origin of the cells involved in this process is still controversial and the relative importance of local expansion versus recruitment of microglia progenitors from the bloodstream is unclear. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of microglia progenitor recruitment from the circulation in denervation or CNS neurodegenerative disease, suggesting that maintenance and local expansion of microglia are solely dependent on the self-renewal of CNS resident cells in these models.

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ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

Yang Shi, Shane Liddelow, Scott T. Smith … (2017)

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective.

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Is Open Access

The UCSC Genome Browser database: extensions and updates 2013

Laurence R. Meyer, Ann Zweig, Angie S. Hinrichs … (2012)

The University of California Santa Cruz (UCSC) Genome Browser (http://genome.ucsc.edu) offers online public access to a growing database of genomic sequence and annotations for a wide variety of organisms. The Browser is an integrated tool set for visualizing, comparing, analysing and sharing both publicly available and user-generated genomic datasets. As of September 2012, genomic sequence and a basic set of annotation ‘tracks’ are provided for 63 organisms, including 26 mammals, 13 non-mammal vertebrates, 3 invertebrate deuterostomes, 13 insects, 6 worms, yeast and sea hare. In the past year 19 new genome assemblies have been added, and we anticipate releasing another 28 in early 2013. Further, a large number of annotation tracks have been either added, updated by contributors or remapped to the latest human reference genome. Among these are an updated UCSC Genes track for human and mouse assemblies. We have also introduced several features to improve usability, including new navigation menus. This article provides an update to the UCSC Genome Browser database, which has been previously featured in the Database issue of this journal.

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Author and article information

Contributors

Tuan Leng Tay: +49 761 270 51060 , tuan.leng.tay@uniklinik-freiburg.de

Dominic Grün: +49 761 270 51060 , gruen@ie-freiburg.mpg.de

Marco Prinz: +49 761 270 51060 , marco.prinz@uniklinik-freiburg.de

Journal

Journal ID (nlm-ta): Acta Neuropathol Commun

Journal ID (iso-abbrev): Acta Neuropathol Commun

Title: Acta Neuropathologica Communications

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-5960

Publication date (Electronic): 5 September 2018

Publication date PMC-release: 5 September 2018

Publication date Collection: 2018

Volume: 6

Electronic Location Identifier: 87

Affiliations

[1 ]GRID grid.5963.9, Institute of Neuropathology, Faculty of Medicine, , University of Freiburg, ; Freiburg, Germany

[2 ]GRID grid.5963.9, Cluster of Excellence BrainLinks-BrainTools, , University of Freiburg, ; Freiburg, Germany

[3 ]GRID grid.5963.9, Institute of Biology I, Faculty of Biology, , University of Freiburg, ; Freiburg, Germany

[4 ]ISNI 0000 0004 0491 4256, GRID grid.429509.3, Max-Planck-Institute of Immunobiology and Epigenetics, ; Freiburg, Germany

[5 ]GRID grid.5963.9, BIOSS Centre for Biological Signaling Studies, , University of Freiburg, ; Freiburg, Germany

Article

Publisher ID: 584

DOI: 10.1186/s40478-018-0584-3

PMC ID: 6123921

PubMed ID: 30185219

SO-VID: b25a0e1c-691c-426a-b46f-3adad4e9e207

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 August 2018

Date accepted : 11 August 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;

Award ID: TA1029/1-1

Award Recipient : Tuan Leng Tay

Funded by: Ministry of Science, Research and the Arts of Baden-Württemberg

Award ID: 7532.21/2.1.6

Award Recipient : Tuan Leng Tay

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Keywords: microglia,recovery,neurodegeneration,single-cell rna analysis

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Keywords: microglia, recovery, neurodegeneration, single-cell rna analysis

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Unique microglia recovery population revealed by single-cell RNAseq following neurodegeneration

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Abstract

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Neuronal Signaling

Most cited references 19

Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.

ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

The UCSC Genome Browser database: extensions and updates 2013

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Cited by 43

Most referenced authors 2,797