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Cell. 2017 Jun 15;169(7):1276-1290.e17. doi: 10.1016/j.cell.2017.05.018. Epub 2017 Jun 8.

A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease.

Author information

1
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
2
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel.
3
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel; Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), and University Medical Center, Cancer Genomics Netherlands, 3584 CG Utrecht, the Netherlands. Electronic address: assaf.weiner@weizmann.ac.il.
4
Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel.
5
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
6
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
7
Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: michal.schwartz@weizmann.ac.il.
8
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: ido.amit@weizmann.ac.il.

Abstract

Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)-/- Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT.

KEYWORDS:

Alzheimer’s disease; immunology; microglia; single cell RNA-seq; systems biology

PMID:
28602351
DOI:
10.1016/j.cell.2017.05.018
[Indexed for MEDLINE]
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