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

Carlo Sala Frigerio; Leen Wolfs; Nicola Fattorelli; Nicola Thrupp; Iryna Voytyuk; Inga Schmidt; Renzo Mancuso; Wei-Ting Chen; Maya E Woodbury; Gyan Srivastava; Thomas Möller; Eloise Hudry; Sudeshna Das; Takaomi Saido; Eric Karran; Bradley Hyman; V Hugh Perry; Mark Fiers; Bart De Strooper

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

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

Authors

Carlo Sala Frigerio¹, Leen Wolfs², Nicola Fattorelli², Nicola Thrupp², Iryna Voytyuk², Inga Schmidt², Renzo Mancuso², Wei-Ting Chen², Maya E Woodbury³, Gyan Srivastava³, Thomas Möller³, Eloise Hudry⁴, Sudeshna Das⁴, Takaomi Saido⁵, Eric Karran³, Bradley Hyman⁴, V Hugh Perry⁶, Mark Fiers², Bart De Strooper⁷

Affiliations

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 App^NL-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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics
Aging / metabolism
Aging / pathology*
Alzheimer Disease / genetics
Alzheimer Disease / metabolism
Alzheimer Disease / pathology*
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / physiology
Animals
Biomarkers / analysis
Biomarkers / metabolism*
Brain / metabolism
Brain / pathology*
Disease Models, Animal*
Female
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout, ApoE
Mice, Transgenic
Microglia / metabolism
Microglia / pathology*
Plaque, Amyloid / genetics
Plaque, Amyloid / metabolism
Plaque, Amyloid / pathology*
Presenilins / physiology
Sex Characteristics

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Biomarkers
Presenilins

Abstract

Publication types

MeSH terms

Substances

Grants and funding