Complement-Mediated Neuroinflammation in Neurodegenerative Diseases

The complement cascade, a proteolytic network originally characterised for host defence, exerts multifaceted roles within the central nervous system. Under physiological conditions, complement components contribute to synaptic refinement, clearance of cellular debris and support of neural plasticity. However, in ageing and neurodegenerative states such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis, dysregulated complement activation drives chronic glial activation, synapse loss and neuronal dysfunction. Elevation of early complement proteins (for example C1q and C3) tags synapses for elimination by microglia and, as recently recognised, by reactive astrocytes. Downstream fragments such as C5a engage receptors on glial populations to amplify pro-inflammatory signalling, establishing a feed-forward loop that exacerbates tissue injury. Increasing evidence from animal models and human tissue reveals that selective modulation of complement receptors and regulators can attenuate pathogenic inflammation while preserving homeostatic roles, positioning complement-directed therapies as promising interventions in neurodegeneration.

Research from Nature Portfolio

Studies using a selective antagonist of the C5a receptor demonstrate that blocking C5aR1 preserves cognitive function and limits detrimental glial polarisation. In an Alzheimer’s disease mouse model, receptor inhibition reduced clusters of neurotoxic microglia, restrained pro-inflammatory astrocyte responses and enhanced gene programmes associated with synaptic support and repair, without affecting beneficial complement functions. Complement C1q has been shown to orchestrate both microglial and astrocytic synapse elimination in tauopathy and amyloid models. Loss of C1q markedly decreases engulfment of excitatory synapses by astrocytes and of inhibitory synapses by microglia, restoring synaptic density and network integrity. Together, these findings highlight cell-type-specific complement mechanisms as viable drug targets.

Complement-Mediated Neuroinflammation in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in complement-mediated neuroinflammation in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Complement system: A cascade of proteolytic proteins forming part of innate immunity that, in the brain, mediates synaptic pruning and inflammatory responses.

C1q: The initial recognition component of the classical complement pathway, critical for tagging synapses and cellular debris for removal.

C5aR1: A receptor for the complement fragment C5a expressed on glial cells, mediating inflammatory signalling.

Microglia: Resident immune cells of the central nervous system responsible for surveillance, phagocytosis and modulation of inflammation.

Astrocyte: A glial cell type involved in synaptic support, neurotransmitter regulation and, upon activation, complement-mediated synapse elimination.

Synaptic pruning: The process by which superfluous or damaged synapses are removed, a normal developmental mechanism that, when dysregulated, contributes to neurodegeneration.

References

1. Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model. Signal Transduction and Targeted Therapy (2023).
2. Complement in the Brain: Contributions to Neuroprotection, Neuronal Plasticity, and Neuroinflammation. Annual Review of Immunology (2023).
3. C5aR1 antagonism suppresses inflammatory glial responses and alters cellular signaling in an Alzheimer’s disease mouse model. Nature Communications (2024).
4. Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models. Nature Aging (2022).
5. Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System. Frontiers in Immunology (2019).
6. The good, the bad, and the opportunities of the complement system in neurodegenerative disease. Journal of Neuroinflammation (2020).