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Nat Med. 2020 Jan;26(1):131-142. doi: 10.1038/s41591-019-0695-9. Epub 2020 Jan 13.

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
2
Bluefin Biomedicine, Beverly, MA, USA.
3
NanoString, Seattle, WA, USA.
4
Pathology Unit, Molecular and Translational Medicine Department, University of Brescia, Brescia, Italy.
5
Department of Chemistry & Biochemistry, University of Missouri-St. Louis, St. Louis, MO, USA.
6
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA.
7
Computer Technologies Department, ITMO University, Saint Petersburg, Russia.
8
Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan.
9
Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
10
Rush Alzheimer's Disease Center and Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
11
Department of Neurology, Hope Center for Neurological Disorders, Knight ADRC, Washington University School of Medicine, St. Louis, MO, USA.
12
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. martyomov@wustl.edu.
13
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. mcolonna@wustl.edu.

Abstract

Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.

PMID:
31932797
PMCID:
PMC6980793
[Available on 2020-07-13]
DOI:
10.1038/s41591-019-0695-9

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