Abstract

The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer’s disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD.

Imbalance of microglial phenotypes in the aging brain might underlie their involvement in late onset neurodegenerative diseases. Here we report the population structure of microglia in the aged human brain and the reduction of a particular microglia subset in individuals with Alzheimer’s disease .

Details

Title
Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease
Author
Olah, Marta 1   VIAFID ORCID Logo  ; Menon Vilas 1   VIAFID ORCID Logo  ; Habib, Naomi 2   VIAFID ORCID Logo  ; Taga, Mariko F 1 ; Ma Yiyi 1   VIAFID ORCID Logo  ; Yung, Christina J 3 ; Cimpean, Maria 3   VIAFID ORCID Logo  ; Khairallah, Anthony 3 ; Coronas-Samano Guillermo 4 ; Sankowski Roman 5   VIAFID ORCID Logo  ; Grün Dominic 6 ; Kroshilina, Alexandra A 3 ; Dionne, Danielle 7   VIAFID ORCID Logo  ; Sarkis, Rani A 8   VIAFID ORCID Logo  ; Cosgrove, Garth R 9 ; Helgager Jeffrey 10 ; Golden, Jeffrey A 10 ; Pennell, Page B 8 ; Prinz, Marco 11   VIAFID ORCID Logo  ; Vonsattel Jean Paul G 4 ; Teich, Andrew F 12   VIAFID ORCID Logo  ; Schneider, Julie A 13 ; Bennett, David A 13 ; Regev Aviv 14   VIAFID ORCID Logo  ; Elyaman Wassim 15 ; Bradshaw, Elizabeth M 15 ; De Jager Philip L 1   VIAFID ORCID Logo 

1  Columbia University Medical Center, Center for Translational and Computational Neuroimmunology, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Columbia University Medical Center, Taub Institute for Research on Alzheimer’s Disease and Aging Brain, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Columbia University Medical Center, Department of Neurology, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Broad Institute, Cell Circuits Program, Cambridge, USA (GRID:grid.66859.34) 
2  Broad Institute, Cell Circuits Program, Cambridge, USA (GRID:grid.66859.34); The Hebrew University of Jerusalem, Edmond & Lily Safra Center for Brain Sciences, Jerusalem, Israel (GRID:grid.9619.7) (ISNI:0000 0004 1937 0538) 
3  Columbia University Medical Center, Center for Translational and Computational Neuroimmunology, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675) 
4  Columbia University Medical Center, Taub Institute for Research on Alzheimer’s Disease and Aging Brain, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Columbia University Medical Center, Department of Pathology and Cell Biology, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675) 
5  University of Freiburg, Institute of Neuropathology, Medical Faculty, Freiburg, Germany (GRID:grid.5963.9); University of Freiburg, Berta-Ottenstein-Programme for Clinician Scientists, Faculty of Medicine, Freiburg, Germany (GRID:grid.5963.9) 
6  Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany (GRID:grid.429509.3) (ISNI:0000 0004 0491 4256) 
7  Broad Institute, Cell Circuits Program, Cambridge, USA (GRID:grid.66859.34) 
8  Brigham and Women’s Hospital, Department of Neurology, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
9  Brigham and Women’s Hospital, Department of Neurosurgery, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
10  Brigham and Women’s Hospital, Department of Pathology, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
11  University of Freiburg, Institute of Neuropathology, Medical Faculty, Freiburg, Germany (GRID:grid.5963.9); University of Freiburg, Signaling Research Centers BIOSS and CIBSS, Freiburg, Germany (GRID:grid.5963.9); University of Freiburg, Center for NeuroModulation, Faculty of Medicine, Freiburg, Germany (GRID:grid.5963.9) 
12  Columbia University Medical Center, Taub Institute for Research on Alzheimer’s Disease and Aging Brain, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Columbia University Medical Center, Department of Neurology, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Columbia University Medical Center, Department of Pathology and Cell Biology, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675) 
13  Rush University Medical Center, Rush Alzheimer’s Disease Center, Chicago, USA (GRID:grid.240684.c) (ISNI:0000 0001 0705 3621) 
14  Broad Institute, Cell Circuits Program, Cambridge, USA (GRID:grid.66859.34); Broad Institute of MIT and Harvard, Klarman Cell Observatory, Cambridge, USA (GRID:grid.66859.34); Department of Biology, MIT, Howard Hughes Medical Institute, Cambridge, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786); Genentech, 1 DNA Way, South San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718) 
15  Columbia University Medical Center, Taub Institute for Research on Alzheimer’s Disease and Aging Brain, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Columbia University Medical Center, Department of Neurology, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Broad Institute, Cell Circuits Program, Cambridge, USA (GRID:grid.66859.34) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-020-19737-2
ProQuest document ID
2473270271
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.