Evidence map›Paper›PMID 40883746›Full record

ArticleMolecular neurodegeneration2025

β-Amyloid induces microglial expression of GPC4 and APOE leading to increased neuronal tau pathology and toxicity.

Brandon B Holmes, Thaddeus K Weigel, Jesseca M Chung, Sarah K Kaufman, Brandon I Apresa, James R Byrnes, Kaan S Kumru, Jaime Vaquer-Alicea, Ankit Gupta, Indigo V L Rose and 12 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular neurodegeneration, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
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

8 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
  4. Article
  5. Review
  6. Review
  7. Article
  8. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

22 authors.

Brandon B HolmesDepartment of Neurology, University of California, San Francisco, San Francisco, CA, 94158, USA.ORCID 0000-0002-1153-840X
Thaddeus K WeigelDepartment of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA.
Jesseca M ChungDepartment of Neurology, University of California, San Francisco, San Francisco, CA, 94158, USA.
Sarah K KaufmanDepartment of Neurology, University of California, San Francisco, San Francisco, CA, 94158, USA.
Brandon I ApresaDepartment of Neurology, University of California, San Francisco, San Francisco, CA, 94158, USA.
James R ByrnesDepartment of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA.
Kaan S KumruDepartment of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA.
Jaime Vaquer-AliceaCenter for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA.
Ankit GuptaCenter for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA.
Indigo V L RoseInstitute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, 94158, USA.
Yun ZhangDepartment of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA.
Alissa L NanaDepartment of Neurology, University of California, San Francisco, San Francisco, CA, 94158, USA.
Dina AlterDepartment of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA.
Lea T GrinbergDepartment of Neurology, University of California, San Francisco, San Francisco, CA, 94158, USA.
Salvatore SpinaDepartment of Neurology, University of California, San Francisco, San Francisco, CA, 94158, USA.
Kevin K LeungDepartment of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA.
Bruce L MillerDepartment of Neurology, University of California, San Francisco, San Francisco, CA, 94158, USA.
Carlo CondelloWeill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, 94158, USA.
Martin KampmannWeill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, 94158, USA.
William W SeeleyDepartment of Neurology, University of California, San Francisco, San Francisco, CA, 94158, USA.
Jaeda C Coutinho-BuddDepartment of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA.
James A WellsDepartment of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA. jim.wells@ucsf.edu.

Funding

Technology and Remote Assessment CoreU19AG063911 · NIA · MAYO CLINIC ROCHESTER · PI ADAM L. BOXER · 2019 to 2026
$120.9M
Early Onset AD Consortium - the LEAD Study (LEADS)U01AG057195 · NIA · INDIANA UNIVERSITY INDIANAPOLIS · PI APOSTOLOVA, LIANA G, CARRILLO, MARIA C · 2018 to 2023
$70.3M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
Research Education ComponentP30AG062422 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Katherine P Rankin · 2019 to 2026
$36.9M
PrPSc SPECIFIC INTERACTION WITH NOVEL PrP-Fc FUSION PROTEINSP50AG023501 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MILLER, BRUCE L · 2004 to 2018
$27.1M
Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSPR01AG060477 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Lea Tenenholz Grinberg, Thomas C Neylan · 2019 to 2026
$8.2M
Surfaceomic technologies and antibodies to probe cell surface proteomes and their interactomes at unprecedented small scale and high-resolutionR35GM122451 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI JAMES A WELLS · 2017 to 2026
$5.3M
Predoctoral Training in NeurobiologyT32NS115706 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI SAMUEL JEREMY PLEASURE · 2020 to 2026
$3.4M
Research Training in Chemistry and Chemical BiologyT32GM145460 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Jason E Gestwicki · 2022 to 2026
$3.1M
Relationships between conformational strains of tau and amyloid-beta, TREM2 and APOE variants, and phenotypic variations of Alzheimer's DiseaseRF1AG061874 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CONDELLO, CARLO L, DEGRADO, WILLIAM · 2018 to 2018
$2.0M
Mechanisms of Glial Interactions and Function at Neuronal Cell BodiesR01NS121101 · NINDS · UNIVERSITY OF VIRGINIA · PI COUTINHO-BUDD, JAEDA · 2021 to 2025
$2.0M
Neuropathological changes underlying clinical heterogeneity in Alzheimer diseaseK24AG053435 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GRINBERG, LEA TENENHOLZ · 2016 to 2025
$1.8M
Alzheimer's Association ZEN-22-969903Brain Institute, University of Virginia Brain Institute, University of VirginiaBrightFocus Foundation BrightFocus FoundationNIA NIH HHS K24 AG053435NIA NIH HHS P01 AG019724NIA NIH HHS P30 AG062422NIA NIH HHS P50 AG023501NIA NIH HHS R01 AG060477NIA NIH HHS RF1 AG061874NIA NIH HHS U01 AG057195NIA NIH HHS U19 AG063911NIGMS NIH HHS R35 GM122451NIGMS NIH HHS R35GM122451NIGMS NIH HHS T32 GM145460NIH HHS K24AG053435NIH HHS P01AG019724NIH HHS P30AG062422NIH HHS RF1AG061874NIH HHS U01AG057195NIH HHS U19AG063911NINDS NIH HHS 1K08NS133290NINDS NIH HHS K08 NS133290NINDS NIH HHS L30 NS134030NINDS NIH HHS R01 NS121101NINDS NIH HHS R01NS121101NINDS NIH HHS T32 NS115706Shenandoah Community Foundation Shenandoah Community Foundation
6 · The paper itself

Abstract

To define how Aβ pathology alters microglia function in Alzheimer’s disease, we profiled the microglia surfaceome following treatment with Aβ fibrils. Our findings reveal that Aβ-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). Glial GPC4 expression exacerbates motor deficits and reduces lifespan in a Drosophila amyloidosis model, implicating GPC4 in a toxic neurodegenerative program. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act in trans to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. In human Alzheimer’s disease brain, microglial GPC4 expression surrounding Aβ plaques correlates with neuritic tau pathology, supporting a pathological link between amyloid, GPC4, and tau. These studies define a mechanistic pathway by which Aβ primes microglia to promote tau pathology via HSPGs and APOE.

Indexed as

Alzheimer DiseaseAmyloid beta-PeptidesApolipoproteins EGlypicansMicrogliaNeuronstau ProteinsAnimalsDrosophilaHumansAmyloid beta-PeptidesApolipoproteins EGlypicanstau ProteinsAlzheimer’s diseaseAmyloidAPOEAstrocytesDrosophila modelGPC4Heparan sulfate proteoglycansMicrogliaNeuroinflammationTau seeding

Identifiers

PMID40883746
PMCPMC12398132

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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.