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Cited by 14Complement system in diseasesNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

The Role of the Complement System in Synaptic Pruning after Stroke

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Liu, Hongying, Jiang, Min, Chen, Zhiying, Li, Chuan, Yin, Xiaoping, Zhang, Xiaorong, Wu, Moxin·2024·Aging and disease
DOI 10.14336/ad.2024.0373PMC PMC12096917
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Abstract

Stroke is a serious disease that can lead to local neurological dysfunction and cause great harm to the patient's health due to blood cerebral circulation disorder. Synaptic pruning is critical for the normal development of the human brain, which makes the synaptic circuit completer and more efficient by removing redundant synapses. The complement system is considered a key player in synaptic loss and cognitive impairment in neurodegenerative disease. After stroke, the complement system is over-activated and complement proteins can be labeled on synapses. Microglia and astrocytes can recognize and engulf synapses through corresponding complement receptors. Complement-mediated excessive synaptic pruning can cause post-stroke cognitive impairment (PSCI) and secondary brain damage. This review summarizes the latest progress of complement-mediated synaptic pruning after stroke and the potential mechanisms. Targeting complement-mediated synaptic pruning may be essential for exploring therapeutic strategies for secondary brain injury (SBI) and neurological dysfunction after stroke.

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  • Complement proteins, particularly C1q and C3, are produced by microglia or astrocytes and localize to apoptotic, immature, or weak developing synapses.

    “Complement proteins, particularly C1q (the initiating protein) and C3, are produced by microglia or astrocytes and localize to apoptotic, immature, or weak developing synapses.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [81]

    The ‘role of C1q in synaptic pruning’ section identifies C1q as the classical complement initiator and says it is derived in part from microglia. The neurodegeneration section says C3 labels weak synapses in the developing visual system. The copy does not establish astrocytes as a source of these proteins or say that the proteins localize to apoptotic or immature synapses; its discussion of apoptotic cells is not a statement about synapses. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Without caspase activity, microglia fail to recognize and eliminate inactive synapses, which is critical for circuit refinement.

    “Without caspase activity, microglia fail to recognize and eliminate inactive synapses, which is critical for circuit refinement [73,81].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [81]

    The 'Overview of synaptic pruning and glia-mediated synaptic pruning' (page not provided) says microglia engulf infrequently used connections to refine synaptic circuits. The copy does not say that this process requires caspase activity or that microglia fail to recognize and eliminate synapses without it (searched: caspase, inactive synapses). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • C1q presynaptic tagging correlates with apoptotic markers, guiding pruning decisions.

    “C1q presynaptic tagging correlates with apoptotic markers, guiding pruning decisions [81,82,83].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [81]

    The sections on C1q and neurodegeneration describe C1q marking synapses before they are engulfed or lost, supporting its role in pruning (page not specified in our copy). They do not identify the tagging as presynaptic or report a correlation between that tagging and apoptotic markers. The separate statement that C1q helps eliminate apoptotic cells does not establish that correlation. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The exact nature of the "punishment signals" that propagate from "winner" to "loser" synapses to drive activity-dependent elimination remains largely unknown.

    “The exact nature of the “punishment signals” that propagate from “winner” to “loser” synapses to drive activity-dependent elimination remains largely unknown [46,80,81].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [81]

    The Overview of synaptic pruning and glia-mediated synaptic pruning (page unavailable) says infrequently used connections are engulfed, supporting the activity-dependent elimination aspect. The section on pruning under physiological conditions describes complement molecules as “eat me” signals, but neither passage addresses signals propagating from “winner” to “loser” synapses or says their exact nature remains unknown. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Synapse elimination is an activity-dependent process where weaker inputs are removed while more active ones are strengthened, a process mediated by synaptic competition in postsynaptic cells.

    “Finally, synapse elimination is an activity-dependent process where weaker inputs are removed while more active ones are strengthened, a process mediated by synaptic competition in postsynaptic cells [46,80,81].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [81]

    The Overview of synaptic pruning and glia-mediated synaptic pruning (page unavailable) says infrequently used connections are engulfed, supporting the removal of weaker inputs. The discussion of neurodegenerative disease likewise describes weak synapses being selectively marked for removal. Our copy does not say that more active inputs are strengthened or that synaptic competition in postsynaptic cells mediates the process. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Liu, H., Jiang, M., Chen, Z., Li, C., Yin, X., Zhang, X., & Wu, M.
Affiliations
Jiujiang University (CN)
Corresponding author
Zhang, Xiaorong
ORCID
Venue
Aging and disease
Publisher
Aging and Disease
Published
2024
Volume
16
Issue
3
Pages
0
ISSN
2152-5250 (ISSN-L)
DOI
10.14336/ad.2024.0373
PMC
PMC12096917
OpenAlex
W4400410558
Cited by
14
References
200
Citations by year
2026: 8 · 2025: 6
FWCI
0.62
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Aging and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
complement system, synaptic pruning, stroke, post-stroke cognitive impairment, secondary brain injury, microglia, astrocytes, complement receptors, neurodegeneration, complement-targeted therapy
MeSH terms
Animals, Astrocytes, Brain, Complement System Proteins, Humans, Neuronal Plasticity, Synapses, Microglia, Stroke, Cognitive Dysfunction

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