title: Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer's disease.
abstract: Amyloid plaques in Alzheimer's disease (AD) mice are surrounded by activated microglia. The functional role of microglia activation in AD is not well understood; both detrimental and beneficial effects on AD progression have been reported. Here we show that the population of activated microglia in the cortex of the APPswe/PS1dE9 mouse AD model is divided into a CD11c-positive and a CD11c-negative subpopulation. Cd11c transcript levels and number of CD11c-positive microglia increase sharply when plaques start to occur and both parameters continue to rise in parallel with the age-related increasing plaque load. CD11c cells are localized near plaques at all stages of the disease development and constitute 23% of all activated microglia. No differences between these two populations were found in terms of proliferation, immunostaining intensity of Iba1, MHC class II, CD45, or immunoproteasome subunit LMP7/β5i. Comparison of the transcriptome of isolated CD11c-positive and CD11c-negative microglia from the cortex of aged APPswe/PS1dE9 with WT microglia showed that gene expression changes had a similar general pattern. However, a differential expression was found for genes involved in immune signaling (Il6, S100a8/Mrp8, S100a9/Mrp14, Spp1, Igf1), lysosome activation, and carbohydrate- and cholesterol/lipid-metabolism (Apoe). In addition, the increased expression of Gpnmb/DC-HIL, Tm7sf4/DC-STAMP, and Gp49a/Lilrb4, suggests a suppressive/tolerizing influence of CD11c cells. We show that amyloid plaques in the APP/PS1 model are associated with two distinct populations of activated microglia: CD11c-positive and CD11c-negative cells. Our findings imply that CD11c-positive microglia can potentially counteract amyloid deposition via increased Aβ-uptake and degradation, and by containing the inflammatory response.
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. Electronic address: w.kamphuis@nin.knaw.nl.
authors.forename: Willem
authors.initials: W
authors.lastname: Kamphuis
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands; Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, The Netherlands.
authors.forename: Lieneke
authors.initials: L
authors.lastname: Kooijman
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Schetters
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands; Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Orre
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands; Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, The Netherlands; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands.
authors.forename: Elly M
authors.initials: EM
authors.lastname: Hol
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D039521:CD11c Antigen / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D039521:CD11c Antigen; D009419:Nerve Tissue Proteins
keywords: Aβ; CD11C; CD11b; Gene expression; Inflammation; Microglia