Atypical chemokine receptor 3 regulates synaptic removal in disease astrocytes
Giusti, V.; Park, J.; Giusto, E.; Masatti, L.; Ramos-Gonzales, P.; Iovino, L.; Sandre, M.; Emmi, A.; Kaur, G.; Coletto, E.; Calura, E.; Petrelli, F.; Porzionato, A.; De Caro, R.; Cavaliere, F.; Civiero, L.
Show abstract
Astrocytes participate in the clearance of obsolete or unwanted neuronal synapses. However, the molecular machinery involved in recognizing these synapses remains unclear, particularly under pathological conditions. Here, we investigated the phagocytic process of astrocytes through individual gene silencing with a druggable gene library. Our study demonstrates that astrocyte- mediated synapse engulfment is regulated by the Atypical chemokine receptor 3 (Ackr3). Mechanistically, we showed that Ackr3 recognizes phosphatidylethanolamine (PE)-bound C-X-C motif chemokine 12 (CXCL12) at synaptic terminals both in vitro and in vivo, thus serving as a novel marker of synaptic dysfunction. Notably, both the receptor and its ligand are upregulated in post- mortem human Alzheimers disease (AD) brains, and AD mouse models. Downregulation of the Ackr3 in AD mice significantly diminishes 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.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Astroglial exosome HepaCAM signaling and ApoE antagonization coordinates early postnatal cortical pyramidal neuronal axon growth and dendritic spine formation 97%
- Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia 97%
- SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration 96%
Similar papers in this journal
- The Integrated Stress Response effector GADD34 is repurposed by neurons to promote stimulus-induced translation 97%
- Neuronal extracellular vesicles mediate BDNF-dependent dendritogenesis and synapse maturation via microRNAs 97%
- ciRS-7 and miR7 regulate ischemia induced neuronal death via glutamatergic signaling 96%
Similar papers in this journal
- MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior 96%
- Sequential replacement of PSD95 subunits in postsynaptic supercomplexes is slowest in the cortex. 96%
- An automated high-content synaptic phenotyping platform in human neurons and astrocytes reveals a role for BET proteins in synapse assembly 96%
Similar papers in this journal
- LRRK2-mutant microglia and neuromelanin synergize to drive dopaminergic neurodegeneration in an iPSC-based Parkinson's disease model 96%
- Polarized ATP synthase in synaptic mitochondria induced by learning and plasticity signals 96%
- Essential roles of plexin-B3+ oligodendrocyte precursor cells in the pathogenesis of Alzheimer's disease 96%
Similar papers in this journal
- Blocking gephyrin phosphorylation or microglia BDNF signaling prevents synapse loss and reduces infarct volume after ischemia 96%
- Astrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines 96%
- Neurons burdened by DNA double strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration. 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.