We have previously developed and characterized isolated microglia and astrocyte cultures from rapid (<4 h) brain autopsies of Alzheimer's disease (AD) and nondemented elderly control (ND) patients. In the present study, we evaluate the inflammatory repertoire of AD and ND microglia cultured from white matter (corpus callosum) and gray matter (superior frontal gyrus) with respect to three major proinflammatory cytokines, three chemokines, a classical pathway complement component, a scavenger cell growth factor, and a reactive nitrogen intermediate. Significant, dose-dependent increases in the production of pro-interleukin-1beta (pro-IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory peptide-1alpha (MIP-1alpha), IL-8, and macrophage colony-stimulating factor (M-CSF) were observed after exposure to pre-aggregated amyloid beta peptide (1-42) (Abeta1-42). Across constitutive and Abeta-stimulated conditions, secretion of complement component C1q, a reactive nitrogen intermediate, and M-CSF was significantly higher in AD compared with ND microglia. Taken together with previous in situ hybridization findings, these results demonstrate unequivocally that elderly human microglia provide a brain endogenous source for a wide range of inflammatory mediators.

• Endothelial S1PR2 plays a critical role in the induction of vascular permeability and vascular inflammation during endotoxemia.• S1PR2 could be a novel therapeutic target to promote vascular integrity in inflammatory vascular disorders.The endothelium, as the interface between blood and all tissues, plays a critical role in inflammation. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid, highly abundant in plasma, that potently regulates endothelial responses through interaction with its receptors (S1PRs). Here, we studied the role of S1PR2 in the regulation of the proadhesion and proinflammatory phenotype of the endothelium. By using genetic approaches and a S1PR2-specific antagonist (JTE013), we found that S1PR2 plays a key role in the permeability and inflammatory responses of the vascular endothelium during endotoxemia. Experiments with bone marrow chimeras (S1pr2 1/1 → S1pr2, and S1pr2 2/2 → S1pr2) indicate the critical role of S1PR2 in the stromal compartment, in the regulation of vascular permeability and vascular inflammation. In vitro, JTE013 potently inhibited tumor necrosis factor a-induced endothelial inflammation. Finally, we provide detailed mechanisms on the downstream signaling of S1PR2 in vascular inflammation that include the activation of the stress-activated protein kinase pathway that, together with the Rho-kinase nuclear factor kappa B pathway (NF-kB), are required for S1PR2-mediated endothelial inflammatory responses. Taken together, our data indicate that S1PR2 is a key regulator of the proinflammatory phenotype of the endothelium and identify S1PR2 as a novel therapeutic target for vascular disorders. (Blood. 2013;122(3):443-455)

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Abstract:In recent years, inflammatory mechanisms have been increasingly appreciated as important steps in the pathology of Alzheimer's disease (AD). There are two pathological defects in AD: chronic inflammation and impaired clearance of amyloid ␤-peptide (A␤). In the periphery, estrogen both increases macrophage phagocytosis and has antiinflammatory effects. If estrogen had a similar effect in the CNS, it could reverse inflammatory defects in AD. Although microglia are a key component of the immune system and help clear A␤ deposits in the AD brain, little is known about the effects of estrogen on CNS microglia. Therefore, we sought to determine the relationship between estrogen treatment and internalization of A␤ by microglia by quantifying the internalization of aggregated A␤ by human cortical microglia. A␤ uptake was found to be dose-and time-dependent in cultured microglia. Increased A␤ uptake was observed at 1.5 and 24 h after addition of aggregated A␤ (50, 100, or 1,000 nM A␤), and this uptake was enhanced by pretreatment with estrogen. The expression of estrogen receptor (ER) ␤ (ER-␤) was also up-regulated by estrogen treatment. Cells cotreated with ICI 182,780, an ER antagonist, showed significantly reduced internalization of A␤ in cultured microglia. These results indicate that microglia express an ER-␤ but that the effect of estrogen on enhancing clearance of A␤ may be related to the receptor-independent action of estrogen or to nonclassical ER effects of estrogen. Thus, stimulation of the ER might contribute to the therapeutic action of estrogen in the treatment of AD.

Our results indicate that relatively low-dose GML consumption promotes metabolic syndrome, gut microbiota dysbiosis, and systemic low-grade inflammation, thereby calling for a reassessment of GML usage.