Publications by authors named "Laura Piccio"

61 Publications

African Americans Have Differences in CSF Soluble TREM2 and Associated Genetic Variants.

Neurol Genet 2021 Apr 4;7(2):e571. Epub 2021 Mar 4.

Department of Neurology (S.E.S., A.J., R.L.H., R.J.M., L.P., J.J.L.-G., K.L.M., A.M.F., D.M.H., J.C.M.), Department of Psychiatry (C.C., F.H.G.F.), and Division of Biostatistics (L.M., C.X.), Washington University School of Medicine, St. Louis, MO; Office of Health Equity and Department of Medicine (C.H.W.), Division of Geriatrics, Vanderbilt University Medical Center, Nashville, TN; Department of Internal Medicine (C.H.W.), Meharry Medical College, Nashville, TN; Alzheimers Disease Research Center (Y.D.), University of Wisconsin School of Medicine and Public Health, Madison; Brain and Mind Centre (L.P.), University of Sydney, NSW, Australia; and Mallinckrodt Institute of Radiology (B.M.A., T.L.S.B.), Washington University School of Medicine, St. Louis, MO.

Objective: To evaluate for racial differences in triggering receptor expressed on myeloid cells 2 (TREM2), a key immune mediator in Alzheimer disease, the levels of CSF soluble TREM2 (sTREM2), and the frequency of associated genetic variants were compared in groups of individuals who self-reported their race as African American (AA) or non-Hispanic White (NHW).

Methods: Community-dwelling older research participants underwent measurement of CSF sTREM2 concentrations and genetic analyses.

Results: The primary cohort included 91 AAs and 868 NHWs. CSF sTREM2 levels were lower in the AA compared with the NHW group (1,336 ± 470 vs 1,856 ± 624 pg/mL, < 0.0001). AAs were more likely to carry coding variants (15% vs 3%, < 0.0001), which were associated with lower CSF sTREM2. AAs were less likely to carry the rs1582763 minor allele (8% vs 37%, < 0.0001), located near , which was associated with higher CSF sTREM2. These findings were replicated in an independent cohort of 23 AAs and 917 NHWs: CSF sTREM2 levels were lower in the AA group ( = 0.03), AAs were more likely to carry coding variants (22% vs 4%, = 0.002), and AAs were less likely to carry the rs1582763 minor allele (16% vs 37%, = 0.003).

Conclusions: On average, AAs had lower CSF sTREM2 levels compared with NHWs, potentially because AAs are more likely to carry genetic variants associated with lower CSF sTREM2 levels. Importantly, CSF sTREM2 reflects TREM2-mediated microglial activity, a critical step in the immune response to amyloid plaques. These findings suggest that race may be associated with risk for genetic variants that influence Alzheimer disease-related inflammation.
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http://dx.doi.org/10.1212/NXG.0000000000000571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054965PMC
April 2021

A new era in neuroimmunology.

J Neuroimmunol 2021 Feb 8;351:577478. Epub 2021 Jan 8.

Center for Neuroimmunology & Neuroinfectious Diseases, Departments of Medicine, Pathology & Immunology, Neurosciences, Washington University School of Medicine, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jneuroim.2021.577478DOI Listing
February 2021

Effects of dietary restriction on neuroinflammation in neurodegenerative diseases.

J Exp Med 2021 Feb;218(2)

Department of Neurology, Washington University in St. Louis, St. Louis, MO.

Recent and accumulating work in experimental animal models and humans shows that diet has a much more pervasive and prominent role than previously thought in modulating neuroinflammatory and neurodegenerative mechanisms leading to some of the most common chronic central nervous system (CNS) diseases. Chronic or intermittent food restriction has profound effects in shaping brain and peripheral metabolism, immunity, and gut microbiome biology. Interactions among calorie intake, meal frequency, diet quality, and the gut microbiome modulate specific metabolic and molecular pathways that regulate cellular, tissue, and organ homeostasis as well as inflammation during normal brain aging and CNS neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, among others. This review discusses these findings and their potential application to the prevention and treatment of CNS neuroinflammatory diseases and the promotion of healthy brain aging.
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http://dx.doi.org/10.1084/jem.20190086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802371PMC
February 2021

Adherence to a healthy lifestyle and multiple sclerosis: a case-control study from the UK Biobank.

Nutr Neurosci 2020 Dec 9:1-9. Epub 2020 Dec 9.

Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.

Background: Multiple sclerosis (MS) is a common and disabling condition. The importance of healthy lifestyle for this disease is poorly explored.

Objective: To test whether adherence to healthier lifestyle patterns is associated with a lower presence of multiple sclerosis (MS).

Methods: By using a case-control design, we investigated the combined association of four healthy lifestyle-related factors (no current smoking, healthy diet, exercising regularly, body mass index <30 kg/m) and the prevalence of MS. A logistic regression analysis, adjusted for potential confounders, was used and data reported as odds ratios (ORs) with their 95% confidence intervals (CIs).

Results: 728 participants with MS were matched with healthy controls ( = 2,912) using a propensity score approach. In a multivariable analysis, compared to those who scored low in the composite lifestyle score (0-1 healthy lifestyle factors), people who adopted all four low risk lifestyle factors showed a 71% lower odds of having MS ( = 0.29; 95% CI: 0.15-0.56). Moreover, there was a strong linear trend, suggesting that the higher number of healthy lifestyle behaviors was associated with lower odds of having MS.

Conclusion: Following a healthy lifestyle is associated with a lower prevalence of MS. This association should be explored further in cohort studies.
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http://dx.doi.org/10.1080/1028415X.2020.1846357DOI Listing
December 2020

Effects of dietary restriction on gut microbiota and CNS autoimmunity.

Clin Immunol 2020 Aug 18:108575. Epub 2020 Aug 18.

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Brain and Mind Centre, University of Sydney, Sydney, NSW 2050, Australia. Electronic address:

Multiple sclerosis (MS) is the most common central nervous system (CNS) autoimmune disease. It is due to the interplay of genetic and environmental factors. Current opinion is that diet could play a pathogenic role in disease onset and development. Dietary restriction (DR) without malnutrition markedly improves health and increases lifespan in multiple model organisms. DR regimens that utilize continuous or intermittent food restriction can induce anti-inflammatory, immuno-modulatory and neuroendocrine adaptations promoting health. These adaptations exert neuroprotective effects in the main MS animal model, experimental autoimmune encephalomyelitis (EAE). This review summarizes the current knowledge on DR-induced changes in gut microbial composition and metabolite production and its impact on underlying functional mechanisms. Studies demonstrating the protective effects of DR regimens on EAE and people with MS are also presented. This is a rapidly developing research field with important clinical implications for personalized dietary interventions in MS prevention and treatment.
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http://dx.doi.org/10.1016/j.clim.2020.108575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889763PMC
August 2020

Higher CSF sTREM2 and microglia activation are associated with slower rates of beta-amyloid accumulation.

EMBO Mol Med 2020 09 10;12(9):e12308. Epub 2020 Aug 10.

Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University (LMU), Munich, Germany.

Microglia activation is the brain's major immune response to amyloid plaques in Alzheimer's disease (AD). Both cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2), a biomarker of microglia activation, and microglia PET are increased in AD; however, whether an increase in these biomarkers is associated with reduced amyloid-beta (Aβ) accumulation remains unclear. To address this question, we pursued a two-pronged translational approach. Firstly, in non-demented and demented individuals, we tested CSF sTREM2 at baseline to predict (i) amyloid PET changes over ∼2 years and (ii) tau PET cross-sectionally assessed in a subset of patients. We found higher CSF sTREM2 associated with attenuated amyloid PET increase and lower tau PET. Secondly, in the App mouse model of amyloidosis, we studied baseline F-GE180 microglia PET and longitudinal amyloid PET to test the microglia vs. Aβ association, without any confounding co-pathologies often present in AD patients. Higher microglia PET at age 5 months was associated with a slower amyloid PET increase between ages 5-to-10 months. In conclusion, higher microglia activation as determined by CSF sTREM2 or microglia PET shows protective effects on subsequent amyloid accumulation.
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http://dx.doi.org/10.15252/emmm.202012308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507349PMC
September 2020

TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis.

Acta Neuropathol 2020 10 9;140(4):513-534. Epub 2020 Aug 9.

Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, proliferation, and phagocytic activity. Herein we demonstrate that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects with TREM2 genetic deficiency displayed a defect in phagocytic pathways. Treatment with a new TREM2 agonistic antibody promoted the clearance of myelin debris in the cuprizone model of CNS demyelination. Effects included enhancement of myelin uptake and degradation, resulting in accelerated myelin debris removal by microglia. Most importantly, antibody-dependent TREM2 activation on microglia increased density of oligodendrocyte precursors in areas of demyelination, as well as the formation of mature oligodendrocytes thus enhancing remyelination and axonal integrity. These results are relevant as they propose TREM2 on microglia as a potential new target to promote remyelination.
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http://dx.doi.org/10.1007/s00401-020-02193-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498497PMC
October 2020

An overview of the current state of evidence for the role of specific diets in multiple sclerosis.

Mult Scler Relat Disord 2019 Nov 9;36:101393. Epub 2019 Sep 9.

Associate Professor of Neurology, Washington University in St. Louis, USA; Brain and Mind Centre, University of Sydney, Australia. Electronic address:

Background: Surveys of people with multiple sclerosis (MS) report that most are interested in using dietary modifications to potentially reduce the severity and symptoms of their disease. This review provides an updated overview of the current state of evidence for the role of specific diets in MS and its animal models, with an emphasis on recent studies including efficacy and safety issues related to dietary manipulations in people with MS.

Methods: Studies were identified using a PubMed search for each diet in both MS and experimental autoimmune encephalomyelitis, by review of the reference list of papers identified in the search process, and by searching clinicaltrials.gov for ongoing studies. Each study was evaluated and the data was summarized. Each diet was assigned a level of evidence for its use in MS based on the Quality Rating Scheme for Studies and Other Evidence.

Results: Several diets have been explored in people with MS and animal models of MS. Most human trials have been small and non-blinded, limiting their generalizability. Many have also been of short-duration, potentially limiting their ability to find clinically meaningful changes. Presently, insufficient evidence exists to recommend the routine use of any specific diet by people with MS. Clinical trials are ongoing or planned for many diets including the Swank Diet, Wahl's diet, McDougall diet, Mediterranean diet, and intermittent fasting. Results of these studies may help guide clinical recommendations.

Conclusion: There is insufficient evidence to recommend the routine use of any specific diet by people with MS. Some diets touted for MS may have potential negative health consequences. It is important that clinicians inquire regarding dietary manipulations, so they can educate patients on any known efficacy data and potential adverse effects of individual diets. Consultation with a registered dietician is recommended for patients undertaking restrictive diets.
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http://dx.doi.org/10.1016/j.msard.2019.101393DOI Listing
November 2019

Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer's disease.

Sci Transl Med 2019 08;11(507)

Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.

Loss of function of TREM2, a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer's disease (AD). We therefore examined whether soluble TREM2 (sTREM2) concentrations in cerebrospinal fluid (CSF) were associated with reduced rates of cognitive decline and clinical progression in subjects with AD or mild cognitive impairment (MCI). We measured sTREM2 in CSF samples from 385 elderly subjects, including cognitively normal controls, individuals with MCI, and subjects with AD dementia (follow-up period: mean, 4 years; range 1.5 to 11.5 years). In subjects with AD defined by evidence of CSF Aβ (amyloid β-peptide 1 to 42; A+) and CSF p-tau (tau phosphorylated on amino acid residue 181; T+), higher sTREM2 concentrations in CSF at baseline were associated with attenuated decline in memory and cognition. When analyzed in clinical subgroups, an association between higher CSF sTREM2 concentrations and subsequent reduced memory decline was consistently observed in individuals with MCI or AD dementia, who were positive for CSF Aβ and CSF p-tau (A+T+). Regarding clinical progression, a higher ratio of CSF sTREM2 to CSF p-tau concentrations predicted slower conversion from cognitively normal to symptomatic stages or from MCI to AD dementia in the subjects who were positive for CSF Aβ and CSF p-tau These results suggest that sTREM2 is associated with attenuated cognitive and clinical decline, a finding with important implications for future clinical trials targeting the innate immune response in AD.
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http://dx.doi.org/10.1126/scitranslmed.aav6221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050285PMC
August 2019

Dietary Intake Regulates the Circulating Inflammatory Monocyte Pool.

Cell 2019 08;178(5):1102-1114.e17

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA. Electronic address:

Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5'-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, we show that fasting improves chronic inflammatory diseases without compromising monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.
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http://dx.doi.org/10.1016/j.cell.2019.07.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357241PMC
August 2019

The gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk.

Sci Transl Med 2019 08;11(505)

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A () gene region were associated with CSF sTREM2 concentrations (rs1582763; = 1.15 × 10); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the and genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with overexpression, and that silencing of reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in risk-variant carriers but also in those with sporadic disease.
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http://dx.doi.org/10.1126/scitranslmed.aau2291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697053PMC
August 2019

T cells producing GM-CSF and IL-13 are enriched in the cerebrospinal fluid of relapsing MS patients.

Mult Scler 2020 09 25;26(10):1172-1186. Epub 2019 Jun 25.

Department of Neurology, School of Medicine, Washington University, St. Louis, MO, USA/Hope Center for Neurological Disorders, School of Medicine, Washington University, St. Louis, MO, USA/Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.

Background: Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune demyelinating disease. Its pathogenesis involves humoral and cellular immunity, with production of pro- and anti-inflammatory cytokines by T cells.

Objective: To analyze the cytokine profile of cerebrospinal fluid (CSF) T cells in patients with relapsing-remitting MS (RRMS) and non-inflammatory controls.

Methods: T cell cytokine production was analyzed by flow cytometry in CSF samples collected from 34 untreated RRMS patients and 20 age-matched controls. Immunofluorescence studies were performed in spinal cord MS active lesions.

Results: Percentages of CSF-derived IL-17A, IL-17A/IL-22, and IL-17A/GM-CSF producing T cells were significantly higher in RRMS patients compared to controls. Percentages of T cells producing IFN-γ were lower in RRMS patients compared to controls. Patients in relapse showed higher percentages of CD4 T cells producing IL-13 and GM-CSF compared to patients in remission. We found a positive correlation between percentages of IL-13 T cells and the Expanded Disability Status Scale (EDSS; ρ = 0.5;  < 0.05). Meningeal IL-13-producing T cells were detected in spinal cord MS active lesions.

Conclusion: We observed differences in IL-17, IL-22, and IFN-γ production by CSF T cells in RRMS versus controls and a positive correlation between IL-13-producing T cells and EDSS in RRMS patients.
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http://dx.doi.org/10.1177/1352458519852092DOI Listing
September 2020

Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology.

Mol Neurodegener 2019 01 10;14(1). Epub 2019 Jan 10.

Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.

Background: TREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid β-peptide (Aβ) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD.

Methods: A cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of Aβ (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score.

Results: CSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal Aβ pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.

Conclusions: Aβ pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, Aβ pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.
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http://dx.doi.org/10.1186/s13024-018-0301-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327425PMC
January 2019

Not only cancer: the long non-coding RNA MALAT1 affects the repertoire of alternatively spliced transcripts and circular RNAs in multiple sclerosis.

Hum Mol Genet 2019 05;28(9):1414-1428

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele Milan, Italy.

Long non-coding RNAs (lncRNAs) are post-transcriptional and epigenetic regulators, whose implication in neurodegenerative and autoimmune diseases remains poorly understood. We analyzed publicly available microarray data sets to identify dysregulated lncRNAs in multiple sclerosis (MS), a neuroinflammatory autoimmune disease. We found a consistent upregulation in MS of the lncRNA MALAT1 (2.7-fold increase; meta-analysis, P = 1.3 × 10-8; 190 cases, 182 controls), known to regulate alternative splicing (AS). We confirmed MALAT1 upregulation in two independent MS cohorts (1.5-fold increase; P < 0.01; 59 cases, 50 controls). We hence performed MALAT1 overexpression/knockdown in cell lines, demonstrating that its modulation impacts on endogenous expression of splicing factors (HNRNPF and HNRNPH1) and on AS of MS-associated genes (IL7R and SP140). Minigene-based splicing assays upon MALAT1 modulation recapitulated IL7R and SP140 isoform unbalances observed in patients. RNA-sequencing of MALAT1-knockdown Jurkat cells further highlighted MALAT1 role in splicing (approximately 1100 significantly-modulated AS events) and revealed its contribution to backsplicing (approximately 50 differentially expressed circular RNAs). Our study proposes a possible novel role for MALAT1 dysregulation and the consequent AS alteration in MS pathogenesis, based on anomalous splicing/backsplicing profiles of MS-relevant genes.
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http://dx.doi.org/10.1093/hmg/ddy438DOI Listing
May 2019

CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM2, neurodegeneration and cognitive decline.

EMBO Mol Med 2018 12;10(12)

Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity-specific manner in AD We measured PGRN in cerebrospinal fluid (CSF) in two of the best-characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross-sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non-carriers 10 years before the expected symptom onset. In late-onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease.
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http://dx.doi.org/10.15252/emmm.201809712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284390PMC
December 2018

Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota.

Cell Metab 2018 Jun;27(6):1222-1235.e6

Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA. Electronic address:

Multiple sclerosis (MS) is more common in western countries with diet being a potential contributing factor. Here we show that intermittent fasting (IF) ameliorated clinical course and pathology of the MS model, experimental autoimmune encephalomyelitis (EAE). IF led to increased gut bacteria richness, enrichment of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families and enhanced antioxidative microbial metabolic pathways. IF altered T cells in the gut with a reduction of IL-17 producing T cells and an increase in regulatory T cells. Fecal microbiome transplantation from mice on IF ameliorated EAE in immunized recipient mice on a normal diet, suggesting that IF effects are at least partially mediated by the gut flora. In a pilot clinical trial in MS patients, intermittent energy restriction altered blood adipokines and the gut flora resembling protective changes observed in mice. In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome.
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http://dx.doi.org/10.1016/j.cmet.2018.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460288PMC
June 2018

The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity.

Immunity 2018 05 8;48(5):979-991.e8. Epub 2018 May 8.

Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano - Milan, Italy; IN-CNR, 20129 Milano, Italy. Electronic address:

The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an increased risk of Alzheimer's disease. Microglial defects in phagocytosis of toxic aggregates or apoptotic membranes were proposed to be at the origin of the pathological processes in the presence of Trem2 inactivating mutations. Here, we show that TREM2 is essential for microglia-mediated synaptic refinement during the early stages of brain development. The absence of Trem2 resulted in impaired synapse elimination, accompanied by enhanced excitatory neurotransmission and reduced long-range functional connectivity. Trem2 mice displayed repetitive behavior and altered sociability. TREM2 protein levels were also negatively correlated with the severity of symptoms in humans affected by autism. These data unveil the role of TREM2 in neuronal circuit sculpting and provide the evidence for the receptor's involvement in neurodevelopmental diseases.
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http://dx.doi.org/10.1016/j.immuni.2018.04.016DOI Listing
May 2018

Use of Vitamins and Dietary Supplements by Patients With Multiple Sclerosis: A Review.

JAMA Neurol 2018 08;75(8):1013-1021

Department of Neurology, Neuroimmunology Section, Washington University in St Louis, St Louis, Missouri.

Importance: Surveys of patients with multiple sclerosis report that most are interested in modifying their diet and using supplements to potentially reduce the severity and symptoms of the disease. This review provides an updated overview of the current state of evidence for the role that vitamins and dietary supplements play in multiple sclerosis and its animal models, with an emphasis on recent studies, and addresses biological plausibility and safety issues.

Observations: Several vitamins and dietary supplements have been recently explored both in animal models and by patients with multiple sclerosis. Most human trials have been small or nonblinded, limiting their generalizability. Biotin and vitamin D are currently being tested in large randomized clinical trials. Smaller trials are ongoing or planned for other supplements such as lipoic acid and probiotics. The results of these studies may help guide clinical recommendations.

Conclusions And Relevance: At the present time, the only vitamin with sufficient evidence to support routine supplementation for patients with multiple sclerosis is vitamin D. Vitamin deficiencies should be avoided. It is important for clinicians to know which supplements their patients are taking and to educate patients on any known efficacy data, along with any potential medication interactions and adverse effects of individual supplements. Given that dietary supplements and vitamins are not subject to the same regulatory oversight as prescription pharmaceuticals in the United States, it is recommended that vitamins and supplements be purchased from reputable manufacturers with the United States Pharmacopeia designation.
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http://dx.doi.org/10.1001/jamaneurol.2018.0611DOI Listing
August 2018

Positive Allosteric Modulation as a Potential Therapeutic Strategy in Anti-NMDA Receptor Encephalitis.

J Neurosci 2018 03 23;38(13):3218-3229. Epub 2018 Feb 23.

Departments of Psychiatry,

-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction. Anti--methyl-d-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden-onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy.
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http://dx.doi.org/10.1523/JNEUROSCI.3377-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596063PMC
March 2018

Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count.

Mult Scler 2018 05 8;24(6):728-738. Epub 2017 May 8.

Department of Neurology, Washington University, St. Louis, MO, USA.

Background: Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about how the drug affects B- and T-lymphocytes.

Objectives: To characterize changes in B- and T-cell phenotype and function induced by DMF and to investigate whether low absolute lymphocyte count (ALC) is associated with unique functional changes.

Methods: Peripheral blood mononuclear cells (PBMCs) were collected from DMF-treated patients, untreated patients, and healthy controls. A subset of DMF-treated patients was lymphopenic (ALC < 800). Multiparametric flow cytometry was used to evaluate cellular phenotypes. Functional response to non-specific and viral peptide stimulation was assessed.

Results: DMF reduced circulating memory B-cells regardless of ALC. Follicular T-helper cells (CD4 CXCR5) and mucosal invariant T-cells (CD8 CD161) were also reduced. DMF reduced T-cell production of pro-inflammatory cytokines in response to polyclonal (PMA/ionomycin) and viral peptide stimulation, regardless of ALC. No differences in activation-induced cell death or circulating progenitors were observed between lymphopenic and non-lymphopenic DMF-treated patients.

Conclusion: These data implicate DMF-induced changes in lymphocytes as an important component of the drug's efficacy and expand our understanding of the functional significance of DMF-induced lymphopenia.
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http://dx.doi.org/10.1177/1352458517707069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665729PMC
May 2018

Mir-223 regulates the number and function of myeloid-derived suppressor cells in multiple sclerosis and experimental autoimmune encephalomyelitis.

Acta Neuropathol 2017 01 4;133(1):61-77. Epub 2016 Oct 4.

Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO, 63110, USA.

Myeloid-derived cells play important modulatory and effector roles in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells, composed of monocytic (MO) and polymorphonuclear (PMN) fractions, which can suppress T cell activities in EAE. Their role in MS remains poorly characterized. We found decreased numbers of circulating MDSCs, driven by lower frequencies of the MO-MDSCs, and higher MDSC expression of microRNA miR-223 in MS versus healthy subjects. To gain mechanistic insights, we interrogated the EAE model. MiR-223 knock out (miR-223) mice developed less severe EAE with increased MDSC numbers in the spleen and spinal cord compared to littermate controls. MiR-223 MO-MDSCs suppressed T cell proliferation and cytokine production in vitro and EAE in vivo more than wild-type MO-MDSCs. They also displayed an increased expression of critical mediators of MDSC suppressive function, Arginase-1(Arg1), and the signal transducer and activator of transcription 3 (Stat3), which herein, we demonstrate being an miR-223 target gene. Consistently, MDSCs from MS patients displayed decreased STAT3 and ARG1 expression compared with healthy controls, suggesting that circulating MDSCs in MS are not only reduced in numbers but also less suppressive. These results support a critical role for miR-223 in modulating MDSC biology in EAE and in MS and suggest potential novel therapeutic applications.
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http://dx.doi.org/10.1007/s00401-016-1621-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423756PMC
January 2017

A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms.

Cell Rep 2016 06 26;15(10):2136-2146. Epub 2016 May 26.

Longevity Institute, School of Gerontology, and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA; Department of Neuroscience, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; IFOM, FIRC Institute of Molecular Oncology, 20139 Milan, Italy. Electronic address:

Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Moreover, the FMD promoted oligodendrocyte precursor cell regeneration and remyelination in axons in both EAE and cuprizone MS models, supporting its effects on both suppression of autoimmunity and remyelination. We also report preliminary data suggesting that an FMD or a chronic ketogenic diet are safe, feasible, and potentially effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) patients (NCT01538355).
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http://dx.doi.org/10.1016/j.celrep.2016.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899145PMC
June 2016

Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status.

Acta Neuropathol 2016 06 11;131(6):925-33. Epub 2016 Jan 11.

Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, Saint Louis, MO, 63110, USA.

Low frequency coding variants in TREM2 are associated with increased Alzheimer disease (AD) risk, while loss of functions mutations in the gene lead to an autosomal recessive early-onset dementia, named Nasu-Hakola disease (NHD). TREM2 can be detected as a soluble protein in cerebrospinal fluid (CSF) and plasma, and its CSF levels are elevated in inflammatory CNS diseases. We measured soluble TREM2 (sTREM2) in the CSF of a large AD case-control dataset (n = 180) and 40 TREM2 risk variant carriers to determine whether CSF sTREM2 levels are associated with AD status or mutation status. We also performed genetic studies to identify genetic variants associated with CSF sTREM2 levels. CSF, but not plasma, sTREM2 was highly correlated with CSF total tau and phosphorylated-tau levels (r = 0.35, P < 1×10(-4); r = 0.40, P < 1×10(-4), respectively), but not with CSF Aβ42. AD cases presented higher CSF sTREM2 levels than controls (P = 0.01). Carriers of NHD-associated TREM2 variants presented significantly lower CSF sTREM2 levels, supporting the hypothesis that these mutations lead to reduced protein production/function (R136Q, D87N, Q33X or T66M; P = 1×10(-3)). In contrast, CSF sTREM2 levels were significantly higher in R47H carriers compared to non-carriers (P = 6×10(-3)), suggesting that this variant does not impact protein expression and increases AD risk through a different pathogenic mechanism than NHD variants. In GWAS analyses for CSF sTREM2 levels the most significant signal was located on the MS4A gene locus (P = 5.45 × 10(-07)) corresponding to one of the SNPs reported to be associated with AD risk in this locus. Furthermore, SNPs involved in pathways related to virus cellular entry and vesicular trafficking were overrepresented, suggesting that CSF sTREM2 levels could be an informative phenotype for AD.
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http://dx.doi.org/10.1007/s00401-016-1533-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867123PMC
June 2016

Predicting optimal response to B-cell depletion with rituximab in multiple sclerosis using CXCL13 index, magnetic resonance imaging and clinical measures.

Mult Scler J Exp Transl Clin 2015 Jan-Dec;1:2055217315623800. Epub 2015 Dec 24.

Department of Neurology, Washington University School of Medicine in St Louis, USA.

Background: B-cell depleting drugs show promise for treating multiple sclerosis.

Objective: We sought predictors of optimal response to rituximab, a B-cell depleting antibody, to help guide therapy selection.

Methods: We performed a post hoc study of 30 relapsing multiple sclerosis patients with breakthrough disease while on beta-interferon or glatiramer acetate who were treated with add-on rituximab. Standardized neurologic examinations, brain magnetic resonance imaging, and cerebrospinal fluid were obtained before and after rituximab. Tissue biomarkers were measured. Optimal responders were defined as having no evidence of disease activity.

Results: At baseline, optimal responders with no evidence of disease activity had higher IgG indices ( = 0.041), and higher CXCL13 indices ((cerebrospinal fluid CXCL13/serum CXCL13)/albumin index;  = 0.024), more contrast enhancing lesions ( = 0.002), better 25 foot timed walk ( = 0.001), and Expanded Disability Status Scale ( = 0.002). Rituximab treatment led to reduced cerebrospinal fluid biomarkers of tissue destruction: myelin basic protein ( = 0.046), neurofilament light chain ( < 0.001), and of inflammation (CXCL13 index;  = 0.042).

Conclusions: Multiple sclerosis patients with optimal response to rituximab had higher cerebrospinal fluid IgG and CXCL13 indices, more gadolinium-enhancing lesions, and less disability at baseline. Rituximab treatment led to decreased markers of inflammation and tissue damage. If validated, these results will help identify multiple sclerosis patients who will respond optimally to B-cell depletion.
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http://dx.doi.org/10.1177/2055217315623800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433328PMC
December 2015

Detection of cortical lesions in multiple sclerosis: A new imaging approach.

Mult Scler J Exp Transl Clin 2015 Jan-Dec;1:2055217315606465. Epub 2015 Sep 24.

Department of Neurology, Washington University School of Medicine in St. Louis, USA.

Cortical lesions occur early in multiple sclerosis (MS) and are thought to have clinical implications. Conventional MRI is insensitive to cortical pathology. Investigational imaging modalities show improved but incomplete cortical lesion detection and are time and resource intensive. Gradient echo plural contrast imaging (GEPCI) is sensitive to MS white matter pathology and can be performed on standard MRI scanners. Here we used GEPCI to examine autopsied MS frontal brain tissues. Two cortical MS lesions were visually distinguished from surrounding tissue by GEPCI and immunohistochemical staining. Furthermore, these lesions were quantitatively differentiated from healthy tissue using GEPCI-derived metrics.
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http://dx.doi.org/10.1177/2055217315606465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433400PMC
September 2015

An ImmunoChip study of multiple sclerosis risk in African Americans.

Brain 2015 Jun 28;138(Pt 6):1518-30. Epub 2015 Mar 28.

1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA

The aims of this study were: (i) to determine to what degree multiple sclerosis-associated loci discovered in European populations also influence susceptibility in African Americans; (ii) to assess the extent to which the unique linkage disequilibrium patterns in African Americans can contribute to localizing the functionally relevant regions or genes; and (iii) to search for novel African American multiple sclerosis-associated loci. Using the ImmunoChip custom array we genotyped 803 African American cases with multiple sclerosis and 1516 African American control subjects at 130 135 autosomal single nucleotide polymorphisms. We conducted association analysis with rigorous adjustments for population stratification and admixture. Of the 110 non-major histocompatibility complex multiple sclerosis-associated variants identified in Europeans, 96 passed stringent quality control in our African American data set and of these, >70% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P < 0.05). At a further eight loci we found nominally significant association with an alternate correlated risk-tagging single nucleotide polymorphism from the same region. Outside the regions known to be associated in Europeans, we found seven potentially associated novel candidate multiple sclerosis variants (P < 10(-4)), one of which (rs2702180) also showed nominally significant evidence for association (one-tailed test P = 0.034) in an independent second cohort of 620 African American cases and 1565 control subjects. However, none of these novel associations reached genome-wide significance (combined P = 6.3 × 10(-5)). Our data demonstrate substantial overlap between African American and European multiple sclerosis variants, indicating common genetic contributions to multiple sclerosis risk.
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http://dx.doi.org/10.1093/brain/awv078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553906PMC
June 2015

TREM2 regulates microglial cell activation in response to demyelination in vivo.

Acta Neuropathol 2015 Mar 29;129(3):429-47. Epub 2015 Jan 29.

Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St Louis, MO, 63110, USA.

Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage.
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http://dx.doi.org/10.1007/s00401-015-1388-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667728PMC
March 2015

Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2.

Mol Neurodegener 2014 Jun 3;9:20. Epub 2014 Jun 3.

Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.

Background: Recent genome-wide association studies linked variants in TREM2 to a strong increase in the odds of developing Alzheimer's disease. The mechanism by which TREM2 influences the susceptibility to Alzheimer's disease is currently unknown. TREM2 is expressed by microglia and is thought to regulate phagocytic and inflammatory microglial responses to brain pathology. Given that a single allele of variant TREM2, likely resulting in a loss of function, conferred an increased risk of developing Alzheimer's disease, we tested whether loss of one functional trem2 allele would affect Aβ plaque deposition or the microglial response to Aβ pathology in APPPS1-21 mice.

Results: There was no significant difference in Aβ deposition in 3-month old or 7-month old APPPS1-21 mice expressing one or two copies of trem2. However, 3-month old mice with one copy of trem2 exhibited a marked decrease in the number and size of plaque-associated microglia. While there were no statistically significant differences in cytokine levels or markers of microglial activation in 3- or 7-month old animals, there were trends towards decreased expression of NOS2, C1qa, and IL1a in 3-month old TREM2+/- vs. TREM2+/+ mice.

Conclusions: Loss of a single copy of trem2 had no effect on Aβ pathology, but altered the morphological phenotype of plaque-associated microglia. These data suggest that TREM2 is important for the microglial response to Aβ deposition but that a 50% decrease inTREM2 expression does not affect Aβ plaque burden.
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http://dx.doi.org/10.1186/1750-1326-9-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049806PMC
June 2014

Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility.

J Clin Invest 2014 Jun 8;124(6):2571-84. Epub 2014 May 8.

Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described. We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease-modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity.
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http://dx.doi.org/10.1172/JCI73408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089451PMC
June 2014