title: Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice.
abstract: Beta-amyloid (Aβ) plaques and chronic neuroinflammation are significant neuropathological features of Alzheimer's disease. Microglial cells in aged brains have potential to produce cytokines such as TNF and IL-1 family members (IL-1α, IL-1β, and IL-1Ra) and to phagocytose Aβ in Alzheimer's disease, however the inter-relationship between these processes is poorly understood. Here we show that % Aβ plaque load followed a sigmoidal trajectory with age in the neocortex of APPswe/PS1ΔE9 Tg mice, and correlated positively with soluble Aβ40 and Aβ42. Aβ measures were moderately correlated with mRNA levels of CD11b, TNF, and IL-1Ra. Cytokine production and Aβ load were assessed in neocortical CD11b(+)(CD45(+)) microglia by flow cytometry. Whereas most microglia in aged mice produced IL-1Ra, relatively low proportions of microglia produced TNF, IL-1α, and IL-1β. However, microglial production of these latter cytokines was generally increased in APP/PS1 Tg mice. Microglia that phagocytosed endogenously-produced Aβ were only observed in APP/PS1 Tg mice. Differences in phagocytic index and total Aβ load were observed in microglia with specific cytokine profiles. Both phagocytic index and total Aβ load were higher in IL-1α(+) and IL-1Ra(+) microglia, than microglia that did not produce these cytokines. In contrast, total Aβ load was lower in IL-1β(+) and TNF(+) microglia, compared to IL-1β(-) and TNF(-) microglia, and TNF(+) microglia also had a lower phagocytic index. Using GFP bone marrow chimeric mice, we confirmed that the majority of neocortical CD11b(+)(CD45(+)) microglia were resident cells (GFP(-)) in APP/PS1 Tg mice, even after selectively analysing CD11b(+)CD45(high) cells, which are typically considered to be infiltrating cells. Together, our data demonstrate that cytokine expression is selectively correlated with age and Aβ pathology, and is associated with an altered Aβ load in phagocytic microglia from APP/PS1 Tg mice. These findings have implications for understanding the regulation of microglial cytokine production and phagocytosis of Aβ in Alzheimer's disease.
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, JB Winsløws Vej 25, 2, 5000 Odense C, Denmark. Electronic address: alicia.a.babcock@gmail.com.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: Babcock
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, JB Winsløws Vej 25, 2, 5000 Odense C, Denmark. Electronic address: lilkjaer@health.sdu.dk.
authors.forename: Laura
authors.initials: L
authors.lastname: Ilkjær
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, JB Winsløws Vej 25, 2, 5000 Odense C, Denmark. Electronic address: bclausen@health.sdu.dk.
authors.forename: Bettina H
authors.initials: BH
authors.lastname: Clausen
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, JB Winsløws Vej 25, 2, 5000 Odense C, Denmark. Electronic address: bivil10@student.sdu.dk.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Villadsen
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, JB Winsløws Vej 25, 2, 5000 Odense C, Denmark. Electronic address: lassedolesen@gmail.com.
authors.forename: Lasse
authors.initials: L
authors.lastname: Dissing-Olesen
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, JB Winsløws Vej 25, 2, 5000 Odense C, Denmark. Electronic address: abendixen@stofanet.dk.
authors.forename: Anita T M
authors.initials: AT
authors.lastname: Bendixen
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, JB Winsløws Vej 25, 2, 5000 Odense C, Denmark. Electronic address: lise@lyck.eu.
authors.forename: Lise
authors.initials: L
authors.lastname: Lyck
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, JB Winsløws Vej 25, 2, 5000 Odense C, Denmark. Electronic address: klambertsen@health.sdu.dk.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Lambertsen
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, JB Winsløws Vej 25, 2, 5000 Odense C, Denmark. Electronic address: bfinsen@health.sdu.dk.
authors.forename: Bente
authors.initials: B
authors.lastname: Finsen
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D053764:Presenilin-1
keywords: Alzheimer’s disease; Flow cytometry; IL-1; IL-1Ra; In vivo; Microglia; Neuroinflammation; Phagocytosis; Stereology; TNF