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Peer-reviewedCC BYMolecular Neurodegeneration

Atypical chemokine receptor 3 regulates synaptic removal in disease astrocytes

  • Veronica Giusti1
  • Jungjoo Park2,3
  • Elena Giusto4
  • Laura Masatti1
  • Paula Ramos‐Gonzalez5
  • Ludovica Iovino6,7
  • Michele Sandre8
  • Aron Emmi9,10
  • Gurkirat Kaur1
  • Erika Coletto4
  • Z. Van Acker11
  • Wim G. Annaert11
7 more authors
  • Enrica Calura1
  • Francesco Petrelli12
  • Andrea Porzionato9,10
  • Raffaele De9,10
  • Fabio Cavaliere5,13
  • WS Chung2,3
  • Laura Civiero1,4,10
13 affiliations
  1. 1Department of Biology, University of Padova, Padova, Italy
  2. 2Center for Vascular Research, Institute for Basic Science (IBS), Daejeon, Republic of Korea
  3. 3Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
  4. 4IRCCS San Camillo Hospital, Venice, Italy
  5. 5Achucarro Basque Centre for Neuroscience, The Basque Biomodels Platform for Human Research Leioa, Spain
  6. 6National Research Council (CNR), Institute of Neuroscience, Pisa, Italy
  7. 7Stella Maris Foundation, IRCCS, Calambrone, Pisa, Italy
  8. 8Department of Neuroscience, University of Padova, Padova 35121, Italy
  9. 9Section of Human Anatomy, Department of Neurosciences, University of Padova, Padua, Italy
  10. 10Study Center for Neurodegeneration (CESNE), Padova, Italy
  11. 11VIB-KU Leuven Center for Brain & Disease Research, Campus Gasthuisberg, Leuven, Belgium
  12. 12Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
  13. 13Fundación Biofisica Bizkaia, Leioa, Spain
Open at sourceDOICite

Abstract

Astrocytes participate in the clearance of obsolete or unwanted neuronal synapses. However, the molecular machinery involved in synapse recognition remains unclear, particularly in pathological conditions. Here, we investigated the phagocytic process of astrocytes through individual gene silencing using a druggable gene library. Our study demonstrates that the Atypical chemokine receptor 3 (Ackr3) is a major player of astrocyte-mediated synapse engulfment. Mechanistically, we showed that Ackr3 recognizes phosphatidylethanolamine (PE)-bound C-X-C motif chemokine 12 (CXCL12) at synaptic terminals, thus serving as a novel marker of synaptic dysfunction. Notably, both ACKR3 and CXCL12 are upregulated in post-mortem brains of Alzheimer's disease (AD) patients, and AD mouse models. Genetic downregulation of Ackr3 in AD mice significantly reduces astrocyte-mediated synaptic elimination and rescues pathological phenotypes, including synapse loss and cognitive impairment. Overall, this work unveils a novel, possibly targetable mechanism of astrocyte-mediated synaptic engulfment implicated in neurodegenerative disease.

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Cite

BibTeXRIS
BibTeX
@article{giusti2026atypical,
  title = {{Atypical chemokine receptor 3 regulates synaptic removal in disease astrocytes}},
  author = {Veronica Giusti and Jungjoo Park and Elena Giusto and Laura Masatti and Paula Ramos‐Gonzalez and Ludovica Iovino and Michele Sandre and Aron Emmi and Gurkirat Kaur and Erika Coletto and Z. Van Acker and Wim G. Annaert and Enrica Calura and Francesco Petrelli and Andrea Porzionato and Raffaele De and Fabio Cavaliere and WS Chung and Laura Civiero},
  journal = {Molecular Neurodegeneration},
  year = {2026},
  month = jul,
  doi = {10.1186/s13024-026-00976-8},
  url = {https://doi.org/10.1186/s13024-026-00976-8},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Atypical chemokine receptor 3 regulates synaptic removal in disease astrocytes
AU  - Veronica Giusti
AU  - Jungjoo Park
AU  - Elena Giusto
AU  - Laura Masatti
AU  - Paula Ramos‐Gonzalez
AU  - Ludovica Iovino
AU  - Michele Sandre
AU  - Aron Emmi
AU  - Gurkirat Kaur
AU  - Erika Coletto
AU  - Z. Van Acker
AU  - Wim G. Annaert
AU  - Enrica Calura
AU  - Francesco Petrelli
AU  - Andrea Porzionato
AU  - Raffaele De
AU  - Fabio Cavaliere
AU  - WS Chung
AU  - Laura Civiero
PY  - 2026
DA  - 2026/07/15
JO  - Molecular Neurodegeneration
DO  - 10.1186/s13024-026-00976-8
UR  - https://doi.org/10.1186/s13024-026-00976-8
AB  - Astrocytes participate in the clearance of obsolete or unwanted neuronal synapses. However, the molecular machinery involved in synapse recognition remains unclear, particularly in pathological conditions. Here, we investigated the phagocytic process of astrocytes through individual gene silencing using a druggable gene library. Our study demonstrates that the Atypical chemokine receptor 3 (Ackr3) is a major player of astrocyte-mediated synapse engulfment. Mechanistically, we showed that Ackr3 recognizes phosphatidylethanolamine (PE)-bound C-X-C motif chemokine 12 (CXCL12) at synaptic terminals, thus serving as a novel marker of synaptic dysfunction. Notably, both ACKR3 and CXCL12 are upregulated in post-mortem brains of Alzheimer's disease (AD) patients, and AD mouse models. Genetic downregulation of Ackr3 in AD mice significantly reduces astrocyte-mediated synaptic elimination and rescues pathological phenotypes, including synapse loss and cognitive impairment. Overall, this work unveils a novel, possibly targetable mechanism of astrocyte-mediated synaptic engulfment implicated in neurodegenerative disease.
SN  - 1750-1326
ER  -