Complement C3aR signaling: Immune and metabolic modulation and its impact on Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia among the elderly population. Despite its widespread prevalence, our comprehension of the intricate mechanisms governing the pathogenesis of the disease remains incomplete, posing a challenge for the development of efficient therapies. Pathologically characterized by the presence of amyloid β plaques and neurofibrillary tau tangles, AD is also accompanied by the hyperactivation of glial cells and the immune system. The complement cascade, the evolutionarily conserved innate immune pathway, has emerged as a significant contributor to AD. This review focuses on one of the complement components, the C3a receptor (C3aR), covering its structure, ligand‐receptor interaction, intracellular signaling and its functional consequences. Drawing insights from cellular and AD mouse model studies, we present the multifaceted role of complement C3aR signaling in AD and attempt to convey to the readers that C3aR acts as a crucial immune and metabolic modulator to influence AD pathogenesis. Building on this framework, the objective of this review is to inform future research endeavors and facilitate the development of therapeutic strategies for this challenging condition.