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APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints

dc.rights.licenseopenen_US
dc.contributor.authorYIN, Zhuoran
dc.contributor.authorROSENZWEIG, Neta
dc.contributor.authorKLEEMANN, Kilian L.
dc.contributor.authorZHANG, Xiaoming
dc.contributor.authorBRANDÃO, Wesley
dc.contributor.authorMARGETA, Milica A.
dc.contributor.authorSCHROEDER, Caitlin
dc.contributor.authorSIVANATHAN, Kisha N.
dc.contributor.authorSILVEIRA, Sebastian
dc.contributor.authorGAUTHIER, Christian
dc.contributor.authorMALLAH, Dania
dc.contributor.authorPITTS, Kristen M.
dc.contributor.authorDURAO, Ana
dc.contributor.authorHERRON, Shawn
dc.contributor.authorSHOREY, Hannah
dc.contributor.authorCHENG, Yiran
dc.contributor.authorBARRY, Jen-Li
dc.contributor.authorKRISHNAN, Rajesh K.
dc.contributor.authorWAKELIN, Sam
dc.contributor.authorRHEE, Jared
dc.contributor.authorYUNG, Anthony
dc.contributor.authorARONCHIK, Michael
dc.contributor.authorWANG, Chao
dc.contributor.authorJAIN, Nimansha
dc.contributor.authorBAO, Xin
dc.contributor.authorGERRITS, Emma
dc.contributor.authorBROUWER, Nieske
dc.contributor.authorDEIK, Amy
dc.contributor.authorTENEN, Daniel G.
dc.contributor.authorIKEZU, Tsuneya
dc.contributor.authorSANTANDER, Nicolas G.
dc.contributor.authorMCKINSEY, Gabriel L.
dc.contributor.authorBAUFELD, Caroline
dc.contributor.authorSHEPPARD, Dean
dc.contributor.authorKRASEMANN, Susanne
dc.contributor.authorNOWARSKI, Roni
dc.contributor.authorEGGEN, Bart J. L.
dc.contributor.authorCLISH, Clary
dc.contributor.authorTANZI, Rudolph E.
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
dc.contributor.authorMADORE, Charlotte
dc.contributor.authorARNOLD, Thomas D.
dc.contributor.authorHOLTZMAN, David M.
dc.contributor.authorBUTOVSKY, Oleg
dc.date.accessioned2023-11-23T14:59:27Z
dc.date.available2023-11-23T14:59:27Z
dc.date.issued2023-09-25
dc.identifier.issn1529-2908en_US
dc.identifier.urioai:crossref.org:10.1038/s41590-023-01627-6
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/186110
dc.description.abstractEnThe APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Here, we show in mice and humans a negative role of microglial APOE4 in the induction of the MGnD response to neurodegeneration. Deletion of microglial APOE4 restores the MGnD phenotype associated with neuroprotection in P301S tau transgenic mice and decreases pathology in APP/PS1 mice. MGnD–astrocyte cross-talk associated with β-amyloid (Aβ) plaque encapsulation and clearance are mediated via LGALS3 signaling following microglial APOE4 deletion. In the brains of AD donors carrying the APOE4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, compared to individuals homozygous for the APOE3 allele. Mechanistically, APOE4-mediated induction of ITGB8–transforming growth factor-β (TGFβ) signaling impairs the MGnD response via upregulation of microglial homeostatic checkpoints, including Inpp5d, in mice. Deletion of Inpp5d in microglia restores MGnD–astrocyte cross-talk and facilitates plaque clearance in APP/PS1 mice. We identify the microglial APOE4–ITGB8–TGFβ pathway as a negative regulator of microglial response to AD pathology, and restoring the MGnD phenotype via blocking ITGB8–TGFβ signaling provides a promising therapeutic intervention for AD.
dc.language.isoENen_US
dc.sourcecrossref
dc.title.enAPOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints
dc.typeArticle de revueen_US
dc.identifier.doi10.1038/s41590-023-01627-6en_US
dc.subject.halSciences du Vivant [q-bio]/Neurosciences [q-bio.NC]en_US
dc.identifier.pubmed37749326en_US
bordeaux.journalNature Immunologyen_US
bordeaux.page1839-1853en_US
bordeaux.volume24en_US
bordeaux.hal.laboratoriesNutriNeuro (Laboratoire de Nutrition et Neurobiologie Intégrée) - UMR 1286en_US
bordeaux.issue11en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionBordeaux INPen_US
bordeaux.institutionINRAEen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcedissemin
hal.identifierhal-04303185
hal.version1
hal.date.transferred2023-11-23T14:59:31Z
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exporttrue
workflow.import.sourcedissemin
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Nature%20Immunology&rft.date=2023-09-25&rft.volume=24&rft.issue=11&rft.spage=1839-1853&rft.epage=1839-1853&rft.eissn=1529-2908&rft.issn=1529-2908&rft.au=YIN,%20Zhuoran&ROSENZWEIG,%20Neta&KLEEMANN,%20Kilian%20L.&ZHANG,%20Xiaoming&BRAND%C3%83O,%20Wesley&rft.genre=article


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