Evidence map›Paper›PMID 40713954›Full record

ArticleNeuron2025

G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation.

Beika Zhu, Andi Wangzhou, Diankun Yu, Tao Li, Rachael Schmidt, Stacy L De Florencio, Lauren Chao, Alicia L Thurber, Minqi Zhou, Zeina Msheik and 8 more

Erratum issuedAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuron, 2025. 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 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing 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

9 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
  4. Article
  5. Article
  6. Review
  7. Article
  8. Microglial phagocytosis in Alzheimer disease.Nature reviews. Neurology · 2026
    Review
  9. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

18 authors.

Beika ZhuWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
Andi WangzhouWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
Diankun YuWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
Tao LiWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
Rachael SchmidtWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.
Stacy L De FlorencioWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.
Lauren ChaoWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.
Alicia L ThurberWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.
Minqi ZhouWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.
Zeina MsheikWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.
Yonatan PerezEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
Lea T GrinbergWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Salvatore SpinaMemory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Richard M RansohoffThird Rock Ventures, Boston, MA 02215, USA.
Arnold R KriegsteinEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
William W SeeleyWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA; Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Tomasz NowakowskiWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA.
Xianhua PiaoWeill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Neonatology, Department of Pediatrics, University of California at San Francisco, San Francisco, CA 94158, USA; Newborn Brain Research Institute, University of California, at San Francisco, San Francisco, CA 94158, USA. Electronic address: xianhua.piao@ucsf.edu.

Funding

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
Adhesion G Protein-Coupled Receptors in CNS Development and RegenerationR01NS094164 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PIAO, XIANHUA · 2015 to 2025
$4.5M
Glial Mechanisms Of Developmental Synapse RefinementR01NS108446 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PIAO, XIANHUA · 2018 to 2022
$2.9M
GPCR-dependent microglial function in Alzheimer's diseaseK99AG081694 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ZHU, BEIKA · 2024 to 2025
$230k
NIA NIH HHS K99 AG081694NIA NIH HHS P01 AG019724NIA NIH HHS P30 AG062422NIA NIH HHS P50 AG023501NINDS NIH HHS R01 NS094164NINDS NIH HHS R01 NS108446
6 · The paper itself

Abstract

Germline genetic architecture of Alzheimer's disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms enabling protective microglial responses remain elusive. Here, we investigate the role of microglial ADGRG1, an adhesion G-protein-coupled receptor (aGPCR) specifically expressed in yolk-sac-derived microglia, in AD pathology using the 5xFAD mouse model. Transcriptomic analyses reveal that ADGRG1 activates the transcription factor MYC, leading to upregulation of genes involved in homeostasis, phagocytosis, and lysosomal functions, thereby promoting a protective microglial state. We demonstrate that deletion of Adgrg1 in microglia impairs MYC activation, resulting in increased amyloid-beta deposition, exacerbated neuronal loss, and cognitive deficits. Functional assays in mouse models and human embryonic stem cell-derived microglia confirm that ADGRG1 is required for Aβ phagocytosis. These findings uncover a GPCR-mediated pathway that drives a protective microglial state via MYC activation, suggesting potential therapeutic strategies to alleviate AD progression by enhancing microglial functional competence.

Indexed as

Alzheimer DiseaseMicrogliaProto-Oncogene Proteins c-mycReceptors, G-Protein-CoupledAmyloid beta-PeptidesAnimalsDisease Models, AnimalHumansMiceMice, TransgenicPhagocytosisAmyloid beta-PeptidesMyc protein, mouseProto-Oncogene Proteins c-mycReceptors, G-Protein-CoupledADGRG1Alzheimer’s diseaseG-protein-coupled receptormicrogliaMYCneurodegenerationphagocytosisβ-amyloid

Identifiers

PMID40713954
PMCPMC12616628

What OpenQuestion holds

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Registered trials

None linked

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.