A double-edged sword: Exploring the neuroprotective/damaging mechanisms of complement activation in Alzheimer's disease

Abstract

• Complement system plays a dual role in the pathogenesis of Alzheimer’s disease (AD): neuroprotective and neurotoxic effects. • Complement components are involved in neuroprotection by clearing abnormal proteins and promoting neuronal repair. • The dysregulation of the complement system may exacerbate inflammation and pathological synaptic pruning. • Complement-targeted therapy offers new insights into the treatment of AD. Alzheimer's disease (AD), the most widespread neurodegenerative disorder afflicting older adults, is characterized by a progressive decline in cognitive function, behavior, and social skills. The complement system, a cornerstone of the innate immune system, plays a crucial role in rapidly recognizing and clearing foreign pathogens, damaged cells, and cellular debris. Recently, there has been growing interest in understanding the intricate roles of complement components in both normal brain development and neurodegenerative processes. We reviewed the activation and role of the complement system in AD, specifically highlighting its stage-dependent functional duality, including both protective and detrimental roles. Furthermore, we assessed current and promising therapeutic strategies targeting complement components in AD. The early stage, defined by pre-plaque pathology, was dominated by protective clearance mechanisms, while the progressive phase, characterized by widespread amyloid and tau pathology, exhibited detrimental neuroinflammation and synaptic loss. Understanding the dual roles of the complement system in AD is crucial for developing targeted therapies.