Abstract

Chronic neuroinflammation is increasingly recognized as a contributor to Alzheimer disease, yet the upstream stimuli that sustain it remain poorly defined. We investigated whether persistent microbial material contributes to Alzheimer disease using the conserved microbial polysaccharide poly-N-acetylglucosamine (PNAG). PNAG-containing microbial material colocalized with amyloid plaques in human Alzheimer disease brain tissue. In fully human neuronal and three-dimensional brain models, purified PNAG and PNAG-containing microbial vesicles activated Toll-like receptor 2-dependent inflammasome signaling and promoted amyloid-{beta} and phosphorylated tau accumulation. Vaccination targeting PNAG improved cognition, reduced glial activation and amyloid pathology, remodeled amyloid processing, and preserved gut microbial community structure in APP/PS1 mice. These findings identify persistent microbial material as an upstream contributor to Alzheimer disease-associated neuroinflammation and a potential therapeutic target.