Biology subjects

Nivet, E.

Publications and source records attributed to Nivet, E..

3 recordsLinked to original sources

bioRxiv2022

High and low permeability of human pluripotent stem cell-derived Blood Brain barrier models depend on epithelial or endothelial features

The search for reliable human blood-brain barrier (BBB) models represents a challenge for the development/testing of strategies aiming to enhance brain delivery of drugs. Human induced pluripotent stem cells (hiPSCs) have raised hopes in the development of predictive BBB models. Differentiating strategies are thus required to generate endothelial cells (ECs), a major component of the BBB. Several hiPSC-based protocols have reported the generation of in vitro models with significant differences in barrier properties. We studied in depth the properties of iPSCs byproducts from two protocols that have been established to yield these in vitro barrier models. Our analysis/study reveals that iPSCs endowed with EC features yield high permeability models, while the cells that exhibit outstanding barrier properties show principally epithelial cell-like (EpC) features. Our study demonstrates that hiPSC-based BBB models need extensive characterization beforehand and that a reliable human BBB model is still needed.

neuroscience↗

bioRxiv2021

The Alzheimer's disease risk factor APOE4 drives pro-inflammation in human astrocytes via HDAC-dependent repression of TAGLN3

The Apolipoprotein E4 (APOE4) is the major allelic risk factor for late-onset Alzheimers disease (AD). APOE4 associates with a pro-inflammatory phenotype increasingly considered as critical in AD initiation and progression. Yet, the mechanisms driving an APOE4-dependent neuroinflammation remain unelucidated. Leveraging patient specific human induced Pluripotent Stem Cells (iPSCs) we demonstrate inflammatory chronicity and hyperactivated responses upon cytokines in human APOE4 astrocytes via a novel mechanism. We uncovered that APOE4 represses Transgelin 3 (TAGLN3), a new interacting partner of I{kappa}B, thus increasing the NF-kB activity. The transcriptional repression of TAGLN3 was shown to result from an APOE4-dependent histone deacetylase (HDAC) activity. The functional relevance of TAGLN3 was demonstrated by the attenuation of APOE4-driven neuroinflammation after TAGLN3 supplementation. Importantly, TAGLN3 downregulation was confirmed in the brain of AD patients. Our findings highlight the APOE4-TAGLN3 axis as a new pathogenic pathway that paves the way for the development of therapeutics to prevent maladaptive inflammatory responses in APOE4 carriers, while placing TAGLN3 downregulation as a potential biomarker of AD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=98 HEIGHT=200 SRC="FIGDIR/small/440108v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1036557org.highwire.dtl.DTLVardef@1f245bdorg.highwire.dtl.DTLVardef@c07c4aorg.highwire.dtl.DTLVardef@1200396_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

MT5-MMP controls APP metabolism and the fate of beta-CTF/C99 and Abeta through proteolytic-dependent and -independent mechanisms relevant for Alzheimer's disease

We previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimers disease AD pathogenesis. Here we shed new light on pathogenic mechanisms by which MT5-MMP controls APP processing and the fate of amyloid beta peptide (A{beta}), its precursor C99 and C83. We found in HEK carrying the APP Swedish familial mutation (HEKswe) that MT5-MMP-mediated processing of APP that releases the soluble 95 kDa form (sAPP95), was hampered by the removal of the C-terminal non-catalytic domains of MT5-MMP. Catalytically inactive MT5-MMP variants increased the levels of A{beta} and promoted APP/C99 sorting in the endo-lysosomal system. We found interaction of C99 with the C-terminal portion of MT5-MMP, the deletion of which caused a strong degradation of C99 by the proteasome, preventing A{beta} accumulation. These findings reveal novel mechanisms for MT5-MMP control of APP metabolism and C99 fate involving proteolytic and non-proteolytic actions mainly mediated by the C-terminal part of the proteinase.

neuroscience↗