Microglial Phenotypes and Functions in Multiple Sclerosis

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Differential contribution of microglia and monocytes in neurodegenerative diseases

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The brain parenchyma has a type I interferon response that can limit virus spread

The brain has a tightly regulated environment that protects neurons and limits inflammation, designated “immune privilege.” However, there is not an absolute lack of an immune response. We tested the ability of the brain to initiate an innate immune response to a virus, which was directly injected into the brain parenchyma, and to determine whether this response could limit viral spread. We injected vesicular stomatitis virus (VSV), a transsynaptic tracer, or naturally occurring VSV-derived defective interfering particles (DIPs), into the caudate–putamen (CP) and scored for an innate immune response and inhibition of virus spread. We found that the brain parenchyma has a functional type I interferon (IFN) response that can limit VSV spread at both the inoculation site and among synaptically connected neurons. Furthermore, we characterized the response of microglia to VSV infection and found that infected microglia produced type I IFN and uninfected microglia induced an innate immune response following virus injection

Human Alzheimer’s disease gene expression signatures and immune profile in APP mouse models: a discrete transcriptomic view of Aβ plaque pathology

Abstract Background Alzheimer’s disease (AD) is a chronic neurodegenerative disease with pathological hallmarks including the formation of extracellular aggregates of amyloid-beta (Aβ) known as plaques and intracellular tau tangles. Coincident with the formation of Aβ plaques is recruitment and activation of glial cells to the plaque forming a plaque niche. In addition to histological data showing the formation of the niche, AD genetic studies have added to the growing appreciation of how dysfunctional glia pathways drive neuropathology, with emphasis on microglia pathways. Genomic approaches enable comparisons of human disease profiles between different mouse models informing on their utility to evaluate secondary changes to triggers such as Aβ deposition. Methods In this study, we utilized two animal models of AD to examine and characterize the AD-associated pathology: the Tg2576 Swedish APP (KM670/671NL) and TgCRND8 Swedish plus Indiana APP (KM670/671NL + V717F) lines. We used laser capture microscopy (LCM) to isolate samples surrounding Thio-S positive plaques from distal non-plaque tissue. These samples were then analyzed using RNA sequencing. Results We determined age-associated transcriptomic differences between two similar yet distinct APP transgenic mouse models, known to differ in proportional amyloidogenic species and plaque deposition rates. In Tg2576, human AD gene signatures were not observed despite profiling mice out to 15 months of age. TgCRND8 mice however showed progressive and robust induction of lysomal, neuroimmune, and ITIM/ITAM-associated gene signatures overlapping with prior human AD brain transcriptomic studies. Notably, RNAseq analyses highlighted the vast majority of transcriptional changes observed in aging TgCRND8 cortical brain homogenates were in fact specifically enriched within the plaque niche samples. Data uncovered plaque-associated enrichment of microglia-related genes such as ITIM/ITAM-associated genes and pathway markers of phagocytosis. Conclusion This work may help guide improved translational value of APP mouse models of AD, particularly for strategies aimed at targeting neuroimmune and neurodegenerative pathways, by demonstrating that TgCRND8 more closely recapitulates specific human AD-associated transcriptional responses

Screening instruments to predict adverse outcomes for undifferentiated older adults attending the Emergency Department: Results of SOAED prospective cohort study

Background: frailty screening facilitates the stratification of older adults at most risk of adverse events for urgent assessment and subsequent intervention. We assessed the validity of the Identification of Seniors at Risk (ISAR), Clinical Frailty Scale (CFS), Programme on Research for Integrating Services for the Maintenance of Autonomy seven item questionnaire (PRISMA-7) and InterRAI-ED at predicting adverse outcomes at 30 days and 6 months amongst older adults presenting to the Emergency Department (ED).Methods: a prospective cohort study of adults ≥65 years who presented to the ED was conducted. The ISAR, CFS, PRISMA-7 and InterRAI-ED were assessed. Blinded follow-up telephone interviews were completed at 30 days and 6 months to assess the incidence of mortality, ED re-attendance, hospital readmission, functional decline and nursing home admission. The sensitivity, specificity, negative predictive value and positive predictive value of the screening tools were calculated using 2 × 2 tables.Results: a total of 419 patients were recruited; 47% female with a mean age of 76.9 (Standard deviation = 7.2). The prevalence of frailty varied across the tools (CFS 57% versus InterRAI-ED 70%). At 30 days, the mortality rate was 5.1%, ED re-attendance 18.1%, hospital readmission 14%, functional decline 47.6% and nursing home admission 7.1%. All tools had a high sensitivity and positive predictive value for predicting adverse outcomes.Conclusion: older adults who screened positive for frailty were at significantly increased risk of experiencing an adverse outcome at 30 days with the ISAR being the most sensitive tool. We would recommend the implementation of the ISAR in the ED setting to support clinicians in identifying older adults most likely to benefit from specialised geriatric assessment and intervention.</p

The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases

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