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

• DOI: 10.1016/j.celrep.2019.03.099
• Publication Date: 2019-04-23T15:04:16Z
• Authors: 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
• Keywords: Male; 570; Aging; PLD3 GENE; Mice, Knockout, ApoE; 610; Mice, Transgenic; Plaque, Amyloid; VARIANTS; AMYLOID HYPOTHESIS; APOLIPOPROTEIN-E; Article; ACTIVATION; Amyloid beta-Protein Precursor; Mice; MOUSE MODELS; Alzheimer Disease; Animals; Humans; RNA-SEQ; DEPOSITION; Sex Characteristics; Science & Technology; Amyloid beta-Peptides; CRUCHAGA; Presenilins; Brain; Cell Biology; 3. Good health; DRUG DISCOVERY; Mice, Inbred C57BL; Disease Models, Animal; Female; Microglia; Life Sciences & Biomedicine; Biomarkers

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.