Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer's disease

TY - JOUR

T1 - Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer's disease

AU - Kamphuis, W.

AU - Kooijman, Lieneke

AU - Schetters, Sjoerd

AU - Orre, Marie

AU - Hol, Elly M

N1 - Copyright © 2016. Published by Elsevier B.V.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1016/j.bbadis.2016.07.007

DO - 10.1016/j.bbadis.2016.07.007

M3 - Article

C2 - 27425031

SN - 0925-4439

VL - 1862

SP - 1847

EP - 1860

JO - Biochimica et Biophysica Acta- Molecular Basis of Disease

JF - Biochimica et Biophysica Acta- Molecular Basis of Disease

ER -