Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice

Beta-amyloid (All) 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-I alpha, IL-10, and IL-1Ra) and to phagocytose A beta in Alzheimer's disease, however the inter-relationship between these processes is poorly understood. Here we show that % All plaque load followed a sigmoidal trajectory with age in the neocortex of APP(swe)/PS1(Delta E9) Tg mice, and correlated positively with soluble A beta 40 and A beta 42. All measures were moderately correlated with mRNA levels of CD11b, TNF, and IL-1Ra. Cytokine production and A beta 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-1 alpha, and IL-1 beta. However, microglial production of these latter cytokines was generally increased in APP/PSI Tg mice. Microglia that phagocytosed endogenously-produced All were only observed in APP/PSI Tg mice. Differences in phagocytic index and total A beta load were observed in microglia with specific cytokine profiles. Both phagocytic index and total A beta load were higher in IL-1 alpha(+) and IL-1Ra(+) microglia, than microglia that did not produce these cytokines. In contrast, total All load was lower in IL-1 beta(+) and TNF+ microglia, compared to IL-1 beta(-) 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/PSI 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 All pathology, and is associated with an altered A beta load in phagocytic microglia from APP/PSI Tg mice. These findings have implications for understanding the regulation of microglial cytokine production and phagocytosis of A beta in Alzheimer's disease. (C) 2015 Elsevier Inc. All rights reserved.