Evidence map›Paper›PMID 37749326›Full record

ArticleNature immunology2023

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

Zhuoran Yin, Neta Rosenzweig, Kilian L Kleemann, Xiaoming Zhang, Wesley Brandão, Milica A Margeta, Caitlin Schroeder, Kisha N Sivanathan, Sebastian Silveira, Christian Gauthier and 33 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature immunology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 146 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
146citing papers in PubMed, 1 pooled it
22.1field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

146 citing papers in PubMed, 1 synthesis or guideline pooled it, 180 citations in OpenAlex.

  1. Pooled it
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86 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

43 authors at 8 institutions in 8 countries.

Zhuoran Yin *Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Neta Rosenzweig *Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Kilian L KleemannDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Xiaoming ZhangDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Wesley BrandãoDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Milica A MargetaDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Caitlin SchroederDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Kisha N SivanathanDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Sebastian SilveiraDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Christian GauthierDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Dania MallahDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Kristen M PittsDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0001-7049-0883
Ana DuraoDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Shawn HerronDepartment of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
Hannah ShoreyDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Yiran ChengDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jen-Li BarryDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Rajesh K KrishnanDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Sam WakelinDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jared RheeDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Anthony YungDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-1338-9401
Michael AronchikDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Chao WangDepartment of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
Nimansha JainDepartment of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
Xin BaoDepartment of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
Emma GerritsDepartment of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Nieske BrouwerDepartment of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Amy DeikBroad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-9687-0953
Daniel G TenenHarvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-6423-3888
Tsuneya IkezuDepartment of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.ORCID 0000-0002-3979-8596
Nicolas G SantanderDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0001-8919-833X
Gabriel L McKinseyDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
Caroline BaufeldDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Dean SheppardDepartment of Medicine, Cardiovascular Research Center, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0002-6277-2036
Susanne KrasemannDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0001-8795-818X
Roni NowarskiDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Bart J L EggenDepartment of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.ORCID 0000-0001-8941-0353
Clary ClishBroad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0001-8259-9245
Rudolph E TanziGenetics and Aging Research Unit, Massachusetts General Hospital, Boston, MA, USA.ORCID 0000-0002-7032-1454
Charlotte MadoreDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Thomas D ArnoldDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
David M HoltzmanDepartment of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
Oleg ButovskyDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. obutovsky@bwh.harvard.edu.ORCID 0000-0003-0186-8867
Brigham and Women's Hospital · USHope Center for Neurological Disorders · USUniversity of California, San Francisco · USUniversity Medical Center Groningen · NLBoston University · USBroad Institute · USHarvard University · USMassachusetts General Hospital · US

Funding

ROLE OF DIETARY CONSTITUENTS ON GENE EXPRESSION IN INTESTINAL EPITHELIUMP30DK040561 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI CHRISTOPHER P DUGGAN · 1994 to 2026
$31.6M
Mass Eye and Ear-Vision Clinical Scientist Development ProgramK12EY016335 · NEI · MASSACHUSETTS EYE AND EAR INFIRMARY · PI Reza Dana · 2004 to 2026
$12.3M
Effect of APOE on CNS Neurons: Role of LRPRF1NS090934 · NINDS · WASHINGTON UNIVERSITY · PI HOLTZMAN, DAVID M. · 2020 to 2025
$6.5M
Targeting TGFb/IFNy-IRF8 Signaling to Modulate Monocytes and their Crosstalk with Microglia and Astrocytes to Treat Multiple SclerosisR01NS088137 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI Oleg Butovsky · 2014 to 2026
$4.9M
Targeting the miR-155 and APOE-TREM2 pathways to restore dysfunctional microglia in Alzheimer’s diseaseR01AG054672 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI BUTOVSKY, OLEG, IKEZU, TSUNEYA · 2017 to 2021
$4.1M
Sex-dependent APOE4 regulation of neutrophil-microglia crosstalk in Alzheimer's diseaseR01AG075509 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI Oleg Butovsky · 2022 to 2026
$3.6M
Role of a novel risk loci HAVCR2 of late-onset Alzheimer's disease in the regulation of microglial response in neurodegenerationR01AG080992 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI Oleg Butovsky, VIJAY K. KUCHROO · 2023 to 2026
$3.3M
Microglial mechanisms of postoperative CNS inflammation and cognitive declineR01AG051812 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI BUTOVSKY, OLEG, CROSBY, GREGORY · 2016 to 2020
$2.7M
Cognition and the immunology of postoperative outcomesR01GM132668 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI CULLEY, DEBORAH J · 2019 to 2024
$2.7M
Role of Microglia in Retinitis PigementosaR01EY027921 · NEI · BRIGHAM AND WOMEN'S HOSPITAL · PI BUTOVSKY, OLEG, HAIDER, NEENA B · 2017 to 2019
$1.5M
The Role of APOE Signaling in Microglia in GlaucomaK08EY030160 · NEI · MASSACHUSETTS EYE AND EAR INFIRMARY · PI MARGETA, MILICA · 2019 to 2021
$703k
Identification of exosome signature in serum from ALS patientsR21NS104609 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI BERRY, JAMES DALE, BUTOVSKY, OLEG · 2018 to 2019
$543k
Alzheimer's Association AARF-21-846786NEI NIH HHS K08 EY030160NEI NIH HHS K12 EY016335NEI NIH HHS R01 EY027921NIA NIH HHS R01 AG051812NIA NIH HHS R01 AG054672NIA NIH HHS R01 AG075509NIA NIH HHS R01 AG080992NIA NIH HHS R21 AG076982NIDDK NIH HHS P30 DK040561NIGMS NIH HHS R01 GM132668NINDS NIH HHS R01 NS088137NINDS NIH HHS R21 NS101673NINDS NIH HHS R21 NS104609NINDS NIH HHS RF1 NS090934
6 · The paper itself

Abstract

The 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.

Indexed as

Alzheimer DiseaseAmyloid beta-PeptidesAnimalsApolipoprotein E4Disease Models, AnimalFemaleGalectin 3HumansMiceMice, TransgenicMicrogliaAmyloid beta-PeptidesApolipoprotein E4Galectin 3

Identifiers

PMID37749326
PMCPMC10863749
OpenAlexW4387012769

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.