title: Distinct inflammatory phenotypes of microglia and monocyte-derived macrophages in Alzheimer's disease models: effects of aging and amyloid pathology.
abstract: Alzheimer's disease (AD) is a neurodegenerative disease characterized by formation of amyloid-β (Aβ) plaques, activated microglia, and neuronal cell death leading to progressive dementia. Recent data indicate that microglia and monocyte-derived macrophages (MDM) are key players in the initiation and progression of AD, yet their respective roles remain to be clarified. As AD occurs mostly in the elderly and aging impairs myeloid functions, we addressed the inflammatory profile of microglia and MDM during aging in TgAPP/PS1 and TgAPP/PS1dE9, two transgenic AD mouse models, compared to WT littermates. We only found MDM infiltration in very aged mice. We determined that MDM highly expressed activation markers at basal state. In contrast, microglia exhibited an activated phenotype only with normal aging and Aβ pathology. Our study showed that CD14 and CD36, two receptors involved in phagocytosis, were upregulated during Aβ pathogenesis. Moreover, we observed, at the protein levels in AD models, higher production of pro-inflammatory mediators: IL-1β, p40, iNOS, CCL-3, CCL-4, and CXCL-1. Taken together, our data indicate that microglia and MDM display distinct phenotypes in AD models and highlight the specific effects of normal aging vs Aβ peptides on inflammatory processes that occur during the disease progression. These precise phenotypes of different subpopulations of myeloid cells in normal and pathologic conditions may allow the design of pertinent therapeutic strategy for AD.
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Martin
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Boucher
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France.|AP-HP, Hôpital de la Pitié Salpêtrière, F-75013, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Delarasse
mesh_terms: D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology; D007249:Inflammation / Q000473:pathology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008264:Macrophages / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology*; D008954:Models, Biological; D009000:Monocytes / Q000473:pathology*; D022423:Myeloid Cells / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010587:Phagocytosis; D010641:Phenotype; D058225:Plaque, Amyloid / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides; D018955:CD36 Antigens; D018925:Chemokines; D018950:Lipopolysaccharide Receptors; D052247:Nitric Oxide Synthase Type II
keywords: Alzheimer's disease; aging; chemokines; cytokines; macrophages; microglia