Meta-Analysis of the Alzheimer\u27s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models.

We present a consensus atlas of the human brain transcriptome in Alzheimer\u27s disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington\u27s disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies

Intrauterine growth retardation induces alterations of colonic epithelial barrier and increases the risk of colonic diseases in adult rats.

Intrauterine growth retardation induces alterations of colonic epithelial barrier and increases the risk of colonic diseases in adult rats.. Colloque fondateur de la SF-DOHa

Le retard de croissance intra-utérin induit des altérations de la barrière épithéliale colique et augmente le risque de pathologie colique chez le rat

Le retard de croissance intra-utérin induit des altérations de la barrière épithéliale colique et augmente le risque de pathologie colique chez le rat. Journées Francophones d’Hépato-Gastroentérologie et d’Oncologie Digestiv

Une dénutrition protéique foetale altère à long terme la barrière épithéliale colique

Une dénutrition protéique foetale altère à long terme la barrière épithéliale colique. 34. Réunion annuelle du Club d'Etudes des Cellules Epithéliales Digestives (CECED

Impact du retard de croissance intra-utérin sur l'hépithélium colique

Impact du retard de croissance intra-utérin sur l'hépithélium colique. 34. Réunion annuelle du Club d'Etudes des Cellules Epithéliales Digestives (CECED

Intrauterine growth retardation alters the colonic epithelial barrier and increases the risk of colonic deseases in adult rats

Intrauterine growth retardation alters the colonic epithelial barrier and increases the risk of colonic deseases in adult rats. United European Gastroenterology Wee

Visceral adipose tissue and leptin increase colonic epithelial tight junction permeability via a RhoA-ROCK-dependent pathway

International audienceProinflammatory cytokines produced by immune cells play a central role in the increased intestinal epithelial permeability during inflammation. Expansion of visceral adipose tissue (VAT) is currently considered a consequence of intestinal inflammation. Whether VAT per se plays a role in early modifications of intestinal barrier remains unknown. The aim of this study was to demonstrate the direct role of adipocytes in regulating paracellular permeability of colonic epithelial cells (CECs). We show in adult rats born with intrauterine growth retardation, a model of VAT hypertrophy, and in rats with VAT graft on the colon, that colonic permeability was increased without any inflammation. This effect was associated with altered expression of tight junction (TJ) proteins occludin and ZO-1. In coculture experiments, adipocytes decreased transepithelial resistance (TER) of Caco-2 CECs and induced a disorganization of ZO-1 on TJs. Intraperitoneal administration of leptin to lean rats increased colonic epithelial permeability and altered ZO-1 expression and organization. Treatment of HT29-19A CECs with leptin, but not adiponectin, dose-dependently decreased TER and altered TJ and F-actin cytoskeleton organization through a RhoA-ROCK-dependent pathway. Our data show that adipocytes and leptin directly alter TJ function in CECs and suggest that VAT could impair colonic epithelial barrier.Le Drean, G., Haure-Mirande, V., Ferrier, L., Bonnet, C., Hulin, P., de Coppet, P., Segain, J.-P. Visceral adipose tissue and leptin increase colonic epithelial tight junction permeability via a RhoA-ROCK-dependent pathway

Gastro-intestinal peptides and first meal pattern following energy restriction in a rat model of intra-uterine growth restriction

Gastro-intestinal peptides and first meal pattern following energy restriction in a rat model of intra-uterine growth restriction. 4. International Conference on Nutrition & Growth Conferenc

Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimers disease.

INTRODUCTION: The inositol polyphosphate-5-phosphatase D (INPP5D) gene encodes a dual-specificity phosphatase that can dephosphorylate both phospholipids and phosphoproteins. Single nucleotide polymorphisms in INPP5D impact risk for developing late onset sporadic Alzheimers disease (LOAD). METHODS: To assess the consequences of inducible Inpp5d knockdown in microglia of APPKM670/671NL /PSEN1Δexon9 (PSAPP) mice, we injected 3-month-old Inpp5dfl/fl /Cx3cr1CreER/+ and PSAPP/Inpp5dfl/fl /Cx3cr1CreER/+ mice with either tamoxifen (TAM) or corn oil (CO) to induce recombination. RESULTS: At age 6 months, we found that the percent area of 6E10+ deposits and plaque-associated microglia in Inpp5d knockdown mice were increased compared to controls. Spatial transcriptomics identified a plaque-specific expression profile that was extensively altered by Inpp5d knockdown. DISCUSSION: These results demonstrate that conditional Inpp5d downregulation in the PSAPP mouse increases plaque burden and recruitment of microglia to plaques. Spatial transcriptomics highlighted an extended gene expression signature associated with plaques and identified CST7 (cystatin F) as a novel marker of plaques. HIGHLIGHTS: Inpp5d knockdown increases plaque burden and plaque-associated microglia number. Spatial transcriptomics identifies an expanded plaque-specific gene expression profile. Plaque-induced gene expression is altered by Inpp5d knockdown in microglia. Our plaque-associated gene signature overlaps with human Alzheimers disease gene networks