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One factor that impacts on microglial activation is the interaction between the ubiquitously expressed CD200 and CD200R, which is expressed only on microglia in the brain. Decreased signalling through CD200R, when CD200 expression is reduced, results in microglial activation and may, at least in part, explain the increased cell activity that is observed with age, in models of Alzheimer's and Parkinson's disease as well as in the human diseases. There is evidence of increased microglial activation in CD200-deficient mice, and isolated microglia prepared from these mice are more reactive to inflammatory stimuli like Toll-like receptor 2 and 4 agonists, and interferon-γ. Here, we examined the impact of CD200 deficiency on amyloid-β (Aβ)-induced changes in microglia and report, perhaps unexpectedly, that the effect of Aβ was attenuated in microglia prepared from CD200-deficient mice. The evidence indicates that this is a consequence of increased phagocytosis, associated with increased lysosomal activity in CD200-deficient microglia. The data suggest that mTOR-related signalling is decreased in these cells and that inhibiting mTOR by rapamycin increases phagocytosis. Thus, while the findings to date have emphasized the anti-inflammatory effects of CD200-CD200R interaction, the present evidence indicates a previously unreported impact on lysosomal function.

There is a wealth of evidence indicating that macrophages adopt distinct phenotypes when exposed to specific stimuli and, in the past few years, accumulating data suggest that microglia behave somewhat similarly. Therefore, microglia can adopt the so-called M1 or M2 phenotypes in response to interferon-γ (IFNγ) and interleukin-4, respectively. Although it has yet to be unequivocally proven in the context of microglia, acutely activated M1 cells are probably protective, although a persistent M1 state is likely to be damaging, whereas M2 cells may be reparative and restorative. In this case, particularly because the current evidence suggests the development of a predominantly M1 state with age and in neurodegenerative diseases, it is important to identify mechanisms by which polarization of microglia can be modulated. The present findings indicate that exposure of cultured microglia to IFNγ increased expressions of the archetypal markers of the M1 phenotype, tumour necrosis factor-α, and inducible nitric oxide synthase, and preexposure of cells to amyloid-β (Aβ) sensitized microglia to subsequent stimulation with IFNγ. Importantly, this synergy was also evident in microglia prepared from the brains of transgenic mice that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1, APP/PS1 mice) and are exposed to a combination of increasing concentrations of endogenous Aβ from 4 or 5 months of age and an age-related increase in IFNγ. Significantly, the JAK2 inhibitor, TG101209, attenuated the IFNγ-induced changes in cultured microglia and in isolated microglia prepared from APP/PS1 mice. These findings suggest that targeting JAK2 may be a potential strategy for reducing neuroinflammation in Alzheimer's disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aging adversely affects inflammatory processes in the brain, which has important implications in the context of disease progression. It has been proposed that microglia become dysfunctional with age and may lose their neuroprotective properties leading to chronic neurodegeneration. Here, we sought to characterize inflammatory changes in a mouse model of Alzheimer's disease and to delineate differences between normal aging and those associated with disease pathology. A proinflammatory profile, characterized by the upregulation of markers of classical activation, was evident in APPswe/PS1dE9 mice, associated with increased interferon-γ (IFNγ) concentration and dysregulation of mechanisms designed to limit the proinflammatory response. The data indicate that microglia are not less active with age but alter their phenotype; indeed, changes observed in the deactivation state appear to relate to aging rather than disease pathology. We hypothesize that disruption of the blood-brain barrier, in tandem with an enhanced chemokine profile, permits the infiltration of immune cells serving to reinforce classical activation of microglia through their enhanced responsiveness to IFNγ., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Peripheral macrophages have limited capacity to gain access to the brain parenchyma under normal physiological conditions. However, accumulating evidence indicates that significant trafficking to the central nervous systems occurs in response to injury or infection and is also apparent under chronic neuroinflammatory conditions. The role of infiltrating macrophages in neuronal function is unclear and confounded by the similarity in morphology and phenotype adopted by both activated macrophages and microglia. Furthermore, the ability of macrophages/microglia to adopt both pro- and anti-inflammatory activation states, along with the fact that these cells display heterogenous expression of molecules associated with both states, has made it difficult to discover their impact upon neuronal injury and cognitive processes. The ability of macrophages to exert a neuroprotective role is influenced by the microenvironment they encounter upon tissue invasion. Upon encountering an inflammatory microenvironment, macrophage polarisation is driven towards a pro-inflammatory (M1) phenotype, a state associated with reduced capacity for restorative processes such as the removal of debris, and enhanced production of pro-inflammatory mediators such as TNFα, IL-1β and NADPH oxidase. Prolonged production of these inflammatory mediators has been shown to affect neuronal function and health. Thus, macrophage polarisation may be dictated by the inflammatory queues these cells are exposed to upon migration and their subsequent impact on neuronal function may be determined by their ability to resolve the underlying inflammation. [ABSTRACT FROM AUTHOR]

The age-related deficit in long-term potentiation (LTP) in the dentate gyrus is positively correlated with hippocampal concentration of the pro-inflammatory cytokine, interleukin-1β (IL-1β). Previous evidence also indicates that the inhibition of LTP induced by intracerebroventricular injection of amyloid-β1–40 (Aβ) is accompanied by increased hippocampal IL-1β concentration and IL-1β-stimulated signalling, specifically activation of the stress-activated protein kinase, c-jun N-terminal kinase (JNK). We considered that the underlying age-related neuroinflammation may render older rats more susceptible to Aβ administration and, to investigate this, young, middle-aged and aged rats were injected intracerebroventricularly with Aβ or vehicle. Hippocampal IL-1β concentration, JNK phosphorylation, expression of the putative Aβ receptor, Receptor for advanced glycation end products (RAGE) and the microglial cell surface marker, CD40 were assessed. We report that Aβ inhibited LTP in a concentration-dependent manner in young rats and that this was accompanied by concentration-dependent increases in hippocampal IL-1β and expression of phosphorylated JNK, RAGE and CD40. While 20 μmol/L Aβ exerted no significant effect on LTP in young rats, it inhibited LTP in middle-aged and aged rats and the increased vulnerability of aged rats was associated with increased IL-1β concentration. Treatment of rats with eicosapentaenoic acid attenuated the inhibitory effect of 60 μmol/L Aβ on LTP in young rats and the effect of 20 μmol/L Aβ in middle-aged and aged rats. We present evidence which indicates that the effect of eicosapentaenoic acid may be linked with its ability to stimulate activation of peroxisome proliferator-activated receptor gamma. [ABSTRACT FROM AUTHOR]

Abstract: Among the changes that occur in the hippocampus with age, is a deficit in long-term potentiation (LTP). This impairment is associated with inflammatory changes, which are typified by increased concentration of the pro-inflammatory cytokine interleukin-1β (IL-1β). Activated microglia are the most likely cell source of IL-1β, but data demonstrating an age-related increase in microglial activation is equivocal. Here we demonstrate that the age-related deficit in LTP is accompanied by increased expression of cell surface markers of activated microglia (major histocompatibility complex II and CD40) and increased IL-1β production, and that these changes may be stimulated by interferon-γ. Treatment of aged rats with eicosapentaenoic acid (EPA) attenuates these changes and we suggest that IL-4 mediates the action of EPA. We demonstrate that aged rats exhibit an exaggerated response to intracerebroventricular injection of β-amyloid peptide 1-40 (Aβ). Thus Aβ inhibited LTP in aged, but not young, rats and induced a further increase in hippocampal IL-1β concentration. Of particular significance is the demonstration that EPA protects the aged brain so that the increased vulnerability to Aβ is ameliorated in EPA-treated rats. [Copyright &y& Elsevier]