Inflammatory microglia are glycolytic and iron retentive and typify the microglia in APP/PS1 mice.

Microglia, like macrophages, can adopt inflammatory and anti-inflammatory phenotypes depending on the stimulus. In macrophages, the evidence indicates that these phenotypes have different metabolic profiles with lipopolysaccharide (LPS)- or interferon-γ (IFNγ)-stimulated inflammatory cells switching to glycolysis as their main source of ATP and interleukin-4 (IL-4)-stimulated cells utilizing oxidative phosphorylation. There is a paucity of information regarding the metabolic signatures of inflammatory and anti-inflammatory microglia. Here, we polarized primary microglia with IFNγ and show that the characteristic increases in tumor necrosis factor-α (TNFα) and nitric oxide synthase 2 (NOS2) were accompanied by increased glycolysis and an increase in the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3, an enzyme that plays a significant role in driving glycolysis. These changes were associated with increased expression of ferritin and retention of iron in microglia. Significantly, retention of iron in microglia increased TNFα expression and also increased glycolysis suggesting that increased intracellular iron concentration may drive the metabolic and/or inflammatory changes. Analysis of microglia prepared from wildtype mice and from transgenic mice that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1) revealed genotype-related increases in glycolysis, accompanied by increased PFKFB3, and an increase in the expression of ferritin. The data indicate a distinct metabolic signature of inflammatory microglia from APP/PS1 mice that are also distinguishable by their iron handling profiles.

Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-ß and cognitive function in APP/PS1 mice.

Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer's disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the disease. This, together with the evidence that genetic variants in the NLRP3 gene impact on the risk of developing late-onset AD, indicates that targetting inflammation offers a therapeutic opportunity. Here, we examined the effect of the small molecule inhibitor of the NLRP3 inflammasome, MCC950, on microglia in vitro and in vivo. The findings indicate that MCC950 inhibited LPS+Aß-induced caspase 1 activation in microglia and this was accompanied by IL-1ß release, without inducing pyroptosis. We demonstrate that MCC950 also inhibited inflammasome activation and microglial activation in the APP/PS1 mouse model of AD. Furthermore, MCC950 stimulated Aß phagocytosis in vitro, and it reduced Aß accumulation in APP/PS1 mice, which was associated with improved cognitive function. These data suggest that activation of the inflammasome contributes to amyloid accumulation and to the deterioration of neuronal function in APP/PS1 mice and demonstrate that blocking assembly of the inflammasome may prove to be a valuable strategy for attenuating changes that negatively impact on neuronal function.

Implicación de la molécula de adhesión ALCAM en el daño cerebral. Modelo de daño neuronal mediante la administración de MDMA/éxtasis en rata / Implication of the adhesion molecule ALCAM in the experimental rat model of brain damage caused by MDMA/ecstasy

Objetivo: Caracterizar la expresión de ALCAM en vasos de corteza cerebral de ratas tratadas con MDMA. 2) Estudiar el efecto que sobre su expresión y sobre la neurotoxicidad producida por MDMA tiene ibuprofeno. Materiales y métodos: Se administró una dosis neurotóxica de MDMA a ratas Dark Agouti e buprofeno a diferentes tiempos. Se midió la temperatura de los animales durante los tratamientos y se estudió la expresión de ALCAM en los vasos de corteza. El daño cerebral se estudió midiendo los niveles de ácido 5-indolacético, serotonina y la densidad de su transportador. Resultados: MDMA produce un aumento de ALCAM a las 24 horas (p<0.01). El co-tratamiento con ibuprofeno lo disminuye (p<0.01) y atenúa el daño cerebral disminuyendo los efectos neurotóxicos de MDMA sobre los niveles de serotonina cortical (p<0.0001) y la densidad del transportador (p<0.0001). Ibuprofeno disminuye ligeramente la hipertermia producida por MDMA. Conclusiones: MDMA aumenta la expresión de ALCAM. Los datos sugieren la posibilidad de utilizar compuestos anti-inflamatorios como ibuprofeno que reducen este efecto sobre ALCAM y que disminuyen parcialmente el daño cerebral, si bien es necesario analizar la participación de la disminución de la temperatura en dicha protección (AU)

Objective: 1) Characterization of ALCAM adhesion molecule expression in cortical vessels of MDMA-treated rats. 2) Study of the effect of the anti-inflammatory compound ibuprofen on ALCAM expression and on the neurotoxicity produced by MDMA. Material and methods: Male Dark Agouti rats were given a neurotoxic dose of MDMA. Ibuprofen was given before and at various times after MDMA. Rectal temperature was monitored during the treatment and ALCAM expression in vessels from cerebral cortex was determined at 24 h. In neurotoxicity studies, cortical 5-HT tissue levels and 5-HT transporter density were measured. Results: ALCAM expression was increased 24 h after MDMA treatment (p<0.01). Co-treatment with ibuprofen attenuated the increase in ALCAM levels (p<0.01) and partially prevented cerebral injury, reducing MDMA-induced 5-HT (p<0.0001) and 5-HT transporter (p<0.0001) loss. Ibuprofen produced a minor modification in the MDMA-induced hyperthermia. Conclusions: Our study demonstrates an effect of MDMA on ALCAM expression. Thus, anti-inflammatory compounds such as ibuprofen may result useful in brain protection by inhibiting the effects of ALCAM and reducing brain damage although the potential contribution of the attenuation of MDMA-induced hyperthermia must also be considered (AU)

CB2 cannabinoid receptors as an emerging target for demyelinating diseases: from neuroimmune interactions to cell replacement strategies.

Amongst the various demyelinating diseases that affect the central nervous system, those induced by an inflammatory response stand out because of their epidemiological relevance. The best known inflammatory-induced demyelinating disease is multiple sclerosis, but the immune response is a common pathogenic mechanism in many other less common pathologies (e.g., acute disseminated encephalomyelitis and acute necrotizing haemorrhagic encephalomyelitis). In all such cases, modulation of the immune response seems to be a logical therapeutic approach. Cannabinoids are well known immunomodulatory molecules that act through CB1 and CB2 receptors. While activation of CB1 receptors has a psychotropic effect, activation of CB2 receptors alone does not. Therefore, to bypass the ethical problems that could result from the treatment of inflammation with psychotropic molecules, considerable effort is being made to study the potential therapeutic value of activating CB2 receptors. In this review we examine the current knowledge and understanding of the utility of cannabinoids as therapeutic molecules for inflammatory-mediated demyelinating pathologies. Moreover, we discuss how CB2 receptor activation is related to the modulation of immunopathogenic states.