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Cell Rep. 2019 Apr 23;27(4):1293-1306.e6. doi: 10.1016/j.celrep.2019.03.099.

The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques.

Author information

1
VIB Centre for Brain Disease Research, Leuven, Belgium; University of Leuven, Department of Neurosciences and Leuven Brain Institute, Leuven, Belgium; UK Dementia Research Institute, University College London, London, UK. Electronic address: carlo.salafrigerio@kuleuven.vib.be.
2
VIB Centre for Brain Disease Research, Leuven, Belgium; University of Leuven, Department of Neurosciences and Leuven Brain Institute, Leuven, Belgium.
3
Foundational Neuroscience Center, AbbVie, Inc., Cambridge, MA, USA.
4
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
5
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
6
UK Dementia Research Institute, University College London, London, UK; Centre for Biological Sciences, University of Southampton, Southampton, UK.
7
VIB Centre for Brain Disease Research, Leuven, Belgium; University of Leuven, Department of Neurosciences and Leuven Brain Institute, Leuven, Belgium; UK Dementia Research Institute, University College London, London, UK. Electronic address: bart.destrooper@kuleuven.vib.be.

Abstract

Gene expression profiles of more than 10,000 individual microglial cells isolated from cortex and hippocampus of male and female AppNL-G-F mice over time demonstrate that progressive amyloid-β accumulation accelerates two main activated microglia states that are also present during normal aging. Activated response microglia (ARMs) are composed of specialized subgroups overexpressing MHC type II and putative tissue repair genes (Dkk2, Gpnmb, and Spp1) and are strongly enriched with Alzheimer's disease (AD) risk genes. Microglia from female mice progress faster in this activation trajectory. Similar activated states are also found in a second AD model and in human brain. Apoe, the major genetic risk factor for AD, regulates the ARMs but not the interferon response microglia (IRMs). Thus, the ARMs response is the converging point for aging, sex, and genetic AD risk factors.

KEYWORDS:

ARM; Alzheimer; IRM; apoe; app knock in; in situ RNA hybridization; microglia; single cell RNA-seq; single cell sequencing

PMID:
31018141
DOI:
10.1016/j.celrep.2019.03.099
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