title: Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer's disease mouse model.
abstract: Pathological hallmarks of Alzheimer's disease (AD) include extracellularly accumulated amyloid β (Aβ) plaques and intracellular neurofibrillary tangles in the brain. Activated microglia, brain-resident macrophages, are also found surrounding Aβ plaques. The study of the brain of AD mouse models revealed that Aβ plaque formation is completed by the consolidation of newly generated plaque clusters in vicinity of existed plaques. However, the dynamics of Aβ plaque formation, growth and the mechanisms by which microglia contribute to Aβ plaque formation are unknown. In the present study, we confirmed how microglia are involved in Aβ plaque formation and their growth in the brain of 5XFAD mice, the Aβ-overexpressing AD transgenic mouse model, and performed serial intravital two-photon microscopy (TPM) imaging of the brains of 5XFAD mice crossed with macrophage/microglia-specific GFP-expressing CX3CR1GFP/GFPmice. We found that activated microglia surrounding Aβ plaques take up Aβ, which are clusters developed inside activated microglia in vivo and this was followed by microglial cell death. These dying microglia release the accumulated Aβ into the extracellular space, which contributes to Aβ plaque growth. This process was confirmed by live TPM in vivo imaging and flow cytometry. These results suggest that activated microglia can contribute to formation and growth of Aβ plaques by causing microglial cell death in the brain. GLIA 2016;64:2274-2290.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, South Korea.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Baik
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, South Korea.
authors.forename: Seokjo
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, South Korea.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Son
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, South Korea. inhee@snu.ac.kr.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D000073883:CX3C Chemokine Receptor 1 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D016207:Cytokines; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D049452:Green Fluorescent Proteins
keywords: Alzheimer's disease; amyloid β plaques; microglia; two-photon in vivo imaging