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Abstract Midlife obesity is a risk factor of late onset Alzheimer's disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, obesity-related neuroinflammation may contribute to damage in limbic structures important in LOAD. Here, we investigated the hypothesis that systemic inflammation would mediate central obesity related effects on limbic tissue microstructure in 166 asymptomatic individuals (38–71 years old). We employed MRI indices sensitive to myelin and neuroinflammation [macromolecular proton fraction (MPF) and k f ] from quantitative magnetization transfer (qMT) together with indices from neurite orientation dispersion and density imaging (NODDI) to investigate the effects of central adiposity on the fornix, parahippocampal cingulum, uncinate fasciculus (compared with whole brain white matter and corticospinal tract) and the hippocampus. Central obesity was assessed with the Waist Hip Ratio (WHR) and abdominal visceral and subcutaneous fat area fractions (VFF, SFF), and systemic inflammation with blood plasma concentrations of leptin, adiponectin, C-reactive protein and interleukin 8. Men were significantly more centrally obese and had higher VFF than women. Individual differences in WHR and in VFF were negatively correlated with differences in fornix MPF and k f , but not with any differences in neurite microstructure. In women, age mediated the effects of VFF on fornix MPF and k f , whilst in men differences in the leptin and adiponectin ratio fully mediated the effect of WHR on fornix MPF. These results suggest that visceral fat related systemic inflammation may damage myelin-related properties of the fornix, a key limbic structure known to be involved in LOAD. Highlights • Central adiposity is linked to apparent myelin/inflammatory damage in the fornix. • Central adiposity is not linked to differences in apparent neurite microstructure. • Men were more centrally obese and had higher visceral fat fractions than women. • In women, age mediated the correlation between visceral fat and fornix myelin. • In men, adipokines mediated the correlation between WHR and fornix myelin. [ABSTRACT FROM AUTHOR]

The Death Receptor 3 (DR3)/Tumour Necrosis Factor-like cytokine 1A (TL1A) axis stimulates effector T cells and type 2 innate lymphocytes (ILC2) that trigger cytokine release and drive disease pathology in several inflammatory and autoimmune diseases, including murine models of acute allergic lung inflammation (ALI). The aim of this study was to elucidate the role of DR3 in chronic ALI compared to acute ALI, using mice genetically deficient in the DR3 gene (DR3 ko ). Results showed DR3 expression in the lungs of wild-type mice was up-regulated following induction of acute ALI and this increased expression was maintained in chronic disease. DR3 ko mice were resistant to cellular accumulation within the alveolar passages in acute, but not chronic ALI. However, DR3 ko mice displayed reduced immuno-histopathology and goblet cell hyperplasia; hallmarks of the asthmatic phenotype; in chronic, but not acute ALI. These data suggest DR3 is a potential therapeutic target, involved in temporally distinct aspects of ALI progression and pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Pre-clinical evaluation of asthma therapies requires animal models of chronic airways inflammation, airway hyperresponsiveness (AHR) and lung remodelling that accurately predict drug effectiveness in human asthma. However, most animal models focus on acute allergen challenges where chronic inflammation and airway remodelling are absent. Chronic allergen challenge models have been developed in mice but few studies use guinea-pigs which may be more relevant to humans. We tested the hypothesis that a chronic rather than acute pulmonary inflammation model would best predict clinical outcome for asthma treatments. Guinea-pigs sensitized with ovalbumin (OVA) received single (acute) or nine OVA inhalation challenges at 48 h intervals (chronic). Airways function was recorded as specific airways conductance (sGaw) in conscious animals for 12 h after OVA challenge. AHR to inhaled histamine, inflammatory cell influx and lung histology were determined 24 h after the single or 9th OVA exposure. The inhaled corticosteroid, fluticasone propionate (FP), the phosphodiesterase 4 inhibitor, roflumilast, and the inducible nitric oxide synthase (iNOS) inhibitor, GW274150, orally, were administered 24 and 0.5 h before and 6 h after the single or final chronic OVA exposure. Both models displayed early (EAR) and late (LAR) asthmatic responses to OVA challenge, as falls in sGaw, AHR, as increased histamine-induced bronchoconstriction, and inflammatory cell influx. Tissue remodelling, seen as increased collagen and goblet cell hyperplasia, occurred after multiple OVA challenge. Treatment with FP and roflumilast inhibited the LAR, cell influx and AHR in both models, and the remodelling in the chronic model. GW274150 also inhibited the LAR, AHR and eosinophil influx in the acute model, but not, together with the remodelling, in the chronic model. In the clinical setting, inhaled corticosteroids and phosphodiesterase 4 inhibitors are relatively effective against most features of asthma whereas the iNOS inhibitor GW274150 was ineffective. Thus, while there remain certain differences between our data and clinical effectiveness of these antiasthma drugs, a chronic pulmonary inflammation guinea-pig model does appear to be a better pre-clinical predictor of potential asthma therapeutics than an acute model. [Copyright &y& Elsevier]

Abstract: Amyloid-β (Aβ) is cleaved from amyloid precursor protein (APP) predominantly after APP has trafficked through the secretory pathway and then become re-internalised by endocytosis. Clathrin-mediated and, more recently, clathrin-independent endocytosis have both been implicated in this process. Furthermore, endocytic abnormalities have been identified in cases of Alzheimer’s disease (AD), however, the relevance of these changes to the aetiology of the disease remains unclear. We therefore examined the expression of proteins related to these endocytic processes in the cortex of Tg2576 mice that overexpress the Swedish mutation in APP, and consequently overexpress Aβ, to determine if there were any changes in their associated pathways. We identified significant increases in the levels of clathrin, dynamin and PICALM, all proteins intimately involved with the clathrin-mediated endocytic pathway, in the transgenic animals. However, levels of proteins associated with flotillin or caveolin-mediated endocytic pathways remained unchanged. These results emphasise the importance of clathrin-mediated endocytosis in the aetiology of AD and reinforce the results of the recent GWAS studies that identified genes for clathrin-mediated endocytosis as susceptibility genes for AD. Such studies in transgenic mice will allow us to learn more about the role of clathrin-mediated endocytosis in AD. [Copyright &y& Elsevier]

Abstract: The mechanisms leading to airway hyper-responsiveness (AHR) in asthma are still not fully understood. AHR could be produced by hypersensitivity of the airway smooth muscle or hyperreactivity of the airways. This study was conducted to ascertain whether AHR in a murine model of asthma is produced by changes at the level of the airway smooth muscle. Airway smooth muscle responses were characterised in vitro in isolated trachea spirals from naive mice and from an acute ovalbumin (OVA) challenge model of allergic asthma. AHR was investigated in vivo in conscious, freely moving mice. Inflammatory cell influx into the lungs and antibody responses to the antigen were also measured. In vitro study of tracheal airway smooth muscle from naïve mice demonstrated concentration-related contractions to methacholine and 5-HT, but no responses to histamine or adenosine or its stable analogue, 5′-N-ethyl-carboxamidoadenosine. The contractions to 5-HT were inhibited by ketanserin and alosetron indicating involvement of 5-HT2A and 5-HT3 receptors, respectively. In an acute model of allergic asthma, OVA-treated mice were shown to be atopic by inflammatory cell influx to the lungs after OVA challenge, increases in total IgE and OVA-specific IgG levels and contractions to OVA in isolated trachea. In the asthmatic model, AHR to methacholine was demonstrated in conscious, freely moving mice in vivo and in isolated trachea in vitro 24 and 72h after OVA challenge. No AHR in vitro was seen for 5-HT, histamine or adenosine. These results suggest that, in our mouse model of asthma, changes occur at the level of the muscarinic receptor transduction pathway of coupling to airway smooth muscle contraction. These changes are maintained when tissues are removed from the inflammatory environment and for at least 3 days. [Copyright &y& Elsevier]