Evidence map›Paper›PMID 33097708›Full record

ArticleNature communications2020

Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer's disease.

Amanda McQuade, You Jung Kang, Jonathan Hasselmann, Amit Jairaman, Alexandra Sotelo, Morgan Coburn, Sepideh Kiani Shabestari, Jean Paul Chadarevian, Gianna Fote, Christina H Tu and 12 more

Erratum issuedOpen access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 222 papers.

0numbers the graph read from it
0cells of the map it votes in
222citing papers in PubMed
15.9field-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

222 citing papers in PubMed, 342 citations in OpenAlex.

  1. Review
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  16. CRISPR-Based Gene Therapy for Brain Disease.Molecular neurobiology · 2026
    Review
  17. Article
  18. Article
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162 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

22 authors at 2 institutions in 3 countries.

Amanda McQuadeDepartment of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.ORCID http://orcid.org/0000-0001-5368-6788
You Jung KangDepartment of Mechanical Engineering and Engineering Science, University of North Carolina Charlotte, Charlotte, NC, 28223, USA.
Jonathan HasselmannDepartment of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.ORCID http://orcid.org/0000-0003-2630-9850
Amit JairamanDepartment of Physiology and Biophysics, University of California Irvine, Irvine, CA, 92697, USA.
Alexandra SoteloSue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.
Morgan CoburnDepartment of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.
Sepideh Kiani ShabestariDepartment of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.
Jean Paul ChadarevianDepartment of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.
Gianna FoteSue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.
Christina H TuSue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.
Emma DanhashSue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.
Jorge SilvaSue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.
Eric MartinezSue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.
Carl CotmanInstitute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, 92697, USA.
G Aleph PrietoInstitute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, 92697, USA.
Leslie M ThompsonDepartment of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.
Joan S SteffanSue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.
Ian SmithDepartment of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.ORCID http://orcid.org/0000-0001-9910-195X
Hayk DavtyanSue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.ORCID http://orcid.org/0000-0001-8554-6456
Michael CahalanDepartment of Physiology and Biophysics, University of California Irvine, Irvine, CA, 92697, USA.
Hansang ChoDepartment of Mechanical Engineering and Engineering Science, University of North Carolina Charlotte, Charlotte, NC, 28223, USA.ORCID http://orcid.org/0000-0003-1829-2462
Mathew Blurton-JonesDepartment of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA. mblurton@uci.edu.ORCID http://orcid.org/0000-0002-7770-7157
University of California, Irvine · USUniversity of North Carolina at Charlotte · US

Funding

Univ.of Calif., Irvine Cancer Center Support GrantP30CA062203 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI Melanie Funes · 1994 to 2026
$57.9M
UC Irvine Alzheimer's Disease Research Center Induced Pluripotent Stem Cell CoreP50AG016573 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI LAFERLA, FRANK M · 2000 to 2019
$37.0M
The Alzheimer's Disease Research Center at the University of California, IrvineP30AG066519 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI Mathew Mark Blurton-Jones · 2020 to 2026
$27.9M
Training in the Neurobiology of Aging and Alzheimers DiseaseT32AG000096 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI VIVEK SWARUP, Craig E Stark · 1985 to 2026
$9.6M
Molecular Mechanisms of lon Channels in T LymphocytesR01NS014609 · NINDS · UNIVERSITY OF CALIFORNIA-IRVINE · PI CAHALAN, MICHAEL D · 1985 to 2022
$7.0M
Training Program in Stem Cell Translational Medicine for Neurological DisordersT32NS082174 · NINDS · UNIVERSITY OF CALIFORNIA-IRVINE · PI PETER John DONOVAN, Leslie Michels Thompson · 2013 to 2026
$3.3M
Using human iPSC derived microglia and chimeric models to examine the role of PLCG2 in Alzheimers diseaseR01AG061895 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI DAVTYAN, HAYK · 2018 to 2022
$2.9M
Cellular and Molecular Mechanisms of Regulatory T Cells in EAER01AI121945 · NIAID · UNIVERSITY OF CALIFORNIA-IRVINE · PI CAHALAN, MICHAEL D · 2016 to 2020
$2.5M
Manipulating DNA repair enzymes to examine the interactions between aging and Alzheimers disease with iPSC-derived microgliaR01AG056303 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI BLURTON-JONES, MATHEW MARK · 2017 to 2021
$1.9M
The role of TREM2 in human microglial function and Alzheimer disease pathogenesisRF1AG048099 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI BLURTON-JONES, MATHEW MARK · 2014 to 2014
$1.9M
PacBio RS Single Molecule, Real-Time (SMRT) DNA SequencerS10OD010794 · OD · UNIVERSITY OF CALIFORNIA-IRVINE · PI SANDMEYER, SUZANNE · 2012 to 2012
$600k
High-Throughput DNA SequencerS10OD021718 · OD · UNIVERSITY OF CALIFORNIA-IRVINE · PI SANDMEYER, SUZANNE · 2016 to 2016
$600k
NCI NIH HHS P30 CA062203NCRR NIH HHS S10 RR025496NIAID NIH HHS R01 AI121945NIA NIH HHS F30 AG060704NIA NIH HHS P30 AG066519NIA NIH HHS P50 AG016573NIA NIH HHS R01 AG056303NIA NIH HHS R01 AG061895NIA NIH HHS R15 AG059236NIA NIH HHS RF1 AG048099NIA NIH HHS T32 AG000096NIH HHS S10 OD010794NIH HHS S10 OD021718NINDS NIH HHS R01 NS014609NINDS NIH HHS T32 NS082174
6 · The paper itself

Abstract

The discovery of TREM2 as a myeloid-specific Alzheimer's disease (AD) risk gene has accelerated research into the role of microglia in AD. While TREM2 mouse models have provided critical insight, the normal and disease-associated functions of TREM2 in human microglia remain unclear. To examine this question, we profile microglia differentiated from isogenic, CRISPR-modified TREM2-knockout induced pluripotent stem cell (iPSC) lines. By combining transcriptomic and functional analyses with a chimeric AD mouse model, we find that TREM2 deletion reduces microglial survival, impairs phagocytosis of key substrates including APOE, and inhibits SDF-1α/CXCR4-mediated chemotaxis, culminating in an impaired response to beta-amyloid plaques in vivo. Single-cell sequencing of xenotransplanted human microglia further highlights a loss of disease-associated microglial (DAM) responses in human TREM2 knockout microglia that we validate by flow cytometry and immunohistochemistry. Taken together, these studies reveal both conserved and novel aspects of human TREM2 biology that likely play critical roles in the development and progression of AD.

Indexed as

Gene Expression RegulationAlzheimer DiseaseAmyloid beta-PeptidesAnimalsBrainCell DeathCell LineChemokine CXCL12ChemotaxisDisease Models, AnimalFemaleGene Knockout TechniquesGenetic Predisposition to DiseaseMaleMembrane GlycoproteinsMiceAmyloid beta-PeptidesChemokine CXCL12CXCR4 protein, mouseMembrane GlycoproteinsReceptors, CXCR4Receptors, ImmunologicTREM2 protein, humanTrem2 protein, mouse

Identifiers

PMID33097708
PMCPMC7584603
OpenAlexW3094535741

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Registered trials

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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.