Gut dysbiosis-driven monocyte reprogramming toward NETotic phenotype accelerates AD pathology

Intestinal barrier dysfunction and LPS translocation primes CCR2+ circulating monocytes and neutrophils toward a NETosis-prone phenotype via TLR4/NF-κB axis activation and PAD4 upregulation. These hyper-NETotic neutrophils exhibit increased CNS trafficking across the compromised blood-brain barrier in AD, depositing granzyme B and chromatin traps that directly induce synaptic damage while triggering persistent microglial activation. The resulting feed-forward loop amplifies neuroinflammation and accelerates amyloid plaque-associated pathology. Testable prediction: inhibiting PAD4 or blocking neutrophil CNS infiltration will reduce neurodegeneration markers and preserve cognitive function in 5xFAD mice colonized with dysbiotic human microbiota.