C3 and C5 complement cascade activation in brain injury and disease: Molecular mechanisms, pathological roles, and...

The complement system represents a crucial component of innate immunity with increasingly recognized roles in central nervous system pathology and homeostasis. Complement components C3 and C5 serve as central molecular hubs in the complement cascade, orchestrating inflammatory responses, synaptic pruning, and neuronal injury across diverse neurological conditions. This comprehensive review examines the molecular mechanisms underlying C3 and C5 activation in the brain, their pathological contributions to acute brain injuries including traumatic brain injury and ischemic stroke, and their complex involvement in chronic neurodegenerative diseases such as Alzheimer disease, multiple sclerosis, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis. Emerging evidence demonstrates that complement activation in the central nervous system extends beyond traditional immune functions to encompass critical roles in neurodevelopment, synaptic plasticity, and neural circuit refinement. The dual nature of complement function in the brain, exhibiting both neuroprotective and neurodegenerative properties depending on context and activation levels, presents unique therapeutic challenges and opportunities. This review synthesizes current understanding of complement-mediated neuroinflammation, discusses validated and emerging therapeutic strategies targeting C3 and C5, evaluates complement biomarkers for disease diagnosis and monitoring, and identifies critical knowledge gaps requiring future investigation. Understanding the nuanced roles of C3 and C5 in neurological disease provides essential foundations for developing targeted immunomodulatory therapies that preserve beneficial complement functions while mitigating pathological activation.