Neuroscience
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Neuroinflammation has long been known as an accompanying pathology of Alzheimer's disease. Microglia surrounding amyloid plaques in the brain of Auguste D were described in the original publication of Alois Alzheimer. ⋯ While gaps in our knowledge remain, and conflicting data are abound in the field, our understanding of the complexities and heterogeneous functions of the inflammatory response in Alzheimer's is vastly improved. This review article will discuss some of the roles of neuroinflammation in Alzheimer's disease, in particular, how understanding heterogeneity in the individual inflammatory response can be used in therapeutic development and as a mechanism of personalizing our treatment of the disease.
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Inflammation has long been associated with the pathogenesis of Parkinson's disease (PD) but the extent to which it is a cause or consequence is sill debated. Over the past decade a number of genes have been implicated in PD. ⋯ Determining how the function of these genes and the proteins they encode are altered in PD has become a priority, as results will likely provide much needed insights into contributing causes. Accumulating evidence indicates that many of these genes function in pathways that regulate aspects of immunity, particularly inflammation, suggesting close associations between PD and immune homeostasis.
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Activation of microglia associated with neuroinflammation and loss of phagocytic activity is considered to play a prominent role in the pathogenesis of Alzheimer's disease (AD). CHF5074 (CSP-1103) has been shown to improve cognition and reduce brain inflammation in patients with mild cognitive impairment (MCI). CHF5074 was also found to reverse impairments in recognition memory and improve hippocampal long-term potentiation when administered to plaque-free Tg2576 mice (5-month-old) for 4 weeks. ⋯ Moreover, CHF5074 significantly increased the expression of anti-inflammatory/phagocytic markers MRC1/CD206 and TREM2, reduced by the Aβ42 application alone. The effect of CHF5074 was not reproduced by ibuprofen (3 μM or 500 μM) or R-flurbiprofen (3 μM or 100 μM), as both compounds limited the pro-inflammatory gene expression but did not modify the anti-inflammatory/phagocytic transcription. These data show that CHF5074 specifically drives the expression of microglia M2 markers either in young Tg2576 hippocampus or in primary astrocyte-microglia cultures, suggesting its potential therapeutic efficacy as microglial modulator in the early phase of AD.
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Repeated social defeat (RSD) in mice causes myeloid cell trafficking to the brain that contributes to the development of prolonged anxiety-like behavior. Myeloid cell recruitment following RSD occurs in regions where neuronal and microglia activation is observed. Thus, we hypothesized that crosstalk between neurons, microglia, and endothelial cells contributes to brain myeloid cell trafficking via chemokine signaling and vascular adhesion molecules. ⋯ While CXCL12 was unaffected by RSD, CCL2 expression was increased by six days of social defeat. Last, comparison between enriched CD11b(+) cells (microglia/macrophages) and enriched GLAST-1(+)/CD11b(-) cells (astrocytes) revealed RSD increased mRNA expression of IL-1β, CCL2, and CXCL2 in microglia/macrophages but not in astrocytes. Collectively, these data indicate that key mediators of leukocyte recruitment were increased in the brain vasculature following RSD in an exposure- and brain region-dependent manner.