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A cortical immune network map identifies a subset of human microglia involved in Tau pathology

Ellis Patrick, Marta Olah, Mariko Taga, Hans-Ulrich Klein, Jishu Xu, Charles C White, Daniel Felsky, Chris Gaiteri, Lori B Chibnik, Sara Mostafavi, Julie A Schneider, David A Bennett, Elizabeth M Bradshaw, Philip L De Jager
doi: https://doi.org/10.1101/234351
Ellis Patrick
1School of Mathematics and Statistics, The University of Sydney, Sydney, Australia
2The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia
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Marta Olah
3Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York City, NY, USA
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Mariko Taga
3Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York City, NY, USA
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Hans-Ulrich Klein
3Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York City, NY, USA
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Jishu Xu
4Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
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Charles C White
4Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
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Daniel Felsky
3Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York City, NY, USA
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Chris Gaiteri
5Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
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Lori B Chibnik
4Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
6Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
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Sara Mostafavi
7Departments of Statistics and Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
8Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada
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Julie A Schneider
5Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
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David A Bennett
5Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
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Elizabeth M Bradshaw
3Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York City, NY, USA
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Philip L De Jager
3Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York City, NY, USA
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Abstract

Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five gene modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 541 subjects from two cohort studies of brain aging. Two of these transcriptional programs – modules 113 and 114 – relate to the accumulation of β-amyloid, while module 5 relates to tau pathology. These modules are also detectable in the human brain's epigenome, where we replicate these associations. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that VASP, a representative module 5 gene, encodes a protein that is upregulated in activated microglia in AD.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 14, 2017.
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A cortical immune network map identifies a subset of human microglia involved in Tau pathology
Ellis Patrick, Marta Olah, Mariko Taga, Hans-Ulrich Klein, Jishu Xu, Charles C White, Daniel Felsky, Chris Gaiteri, Lori B Chibnik, Sara Mostafavi, Julie A Schneider, David A Bennett, Elizabeth M Bradshaw, Philip L De Jager
bioRxiv 234351; doi: https://doi.org/10.1101/234351
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A cortical immune network map identifies a subset of human microglia involved in Tau pathology
Ellis Patrick, Marta Olah, Mariko Taga, Hans-Ulrich Klein, Jishu Xu, Charles C White, Daniel Felsky, Chris Gaiteri, Lori B Chibnik, Sara Mostafavi, Julie A Schneider, David A Bennett, Elizabeth M Bradshaw, Philip L De Jager
bioRxiv 234351; doi: https://doi.org/10.1101/234351

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