Monomeric C-Reactive Protein Potentiates Microglia-Mediated Neuroinflammation in Alzheimer's Disease via the...

Neuroinflammation is a major contributor to the pathogenesis of Alzheimer's disease (AD). Although elevated serum C-reactive protein (CRP) is associated with increased AD risk, the specific conformational forms of CRP operative in the brain and their underlying mechanisms remain unclear. Here, we combined human brain transcriptomic analysis, APP/PS1 mice studies, and functional assays in BV2 cells and primary microglia to elucidate the roles of CRP and its monomeric form (mCRP) in AD-related neuroinflammation. CRP was significantly upregulated in the brains of AD patients and in the hippocampus of APP/PS1 mice, where it extensively co-localized with activated microglia. mCRP directly induced M1 pro-inflammatory microglial polarization and synergistically enhanced neuroinflammation with amyloid-β₄₂-derived diffusible ligands (ADDLs). Additionally, mCRP dissipated mitochondrial membrane potential and promoted intracellular and mitochondrial reactive oxygen species accumulation. Mechanistically, mCRP activated the phospholipase C (PLC)-protein kinase C (PKC)-mitogen-activated protein kinase (MAPK)-nuclear factor-κB (NF-κB) signaling cascade, whereas the PLC inhibitor U-73122 attenuated pathway activation and reduced the production of pro-inflammatory cytokines. Collectively, these findings identify mCRP as a critical mediator linking systemic inflammation to microglia-driven neuroinflammation in AD, offering new mechanistic insights into AD pathogenesis.