Vaccination against the broadly expressed microbial antigen PNAG prevents cognitive decline in the APP-PS1 mouse model of Alzheimer's disease.

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While there is ample evidence for a role of the microbiota in cognitive decline in Alzheimer's Disease (AD), there is little insight into how the microbiota mediates neuronal dysfunction and cognitive decline. A conserved surface polysaccharide, poly-N-acetyl glucosamine (PNAG) is produced by a broad range of microbial cells, but not mammals. We have detected the presence of PNAG-positive, likely microbiota-derived cells or fragments closely associated with amyloid-ß deposits in the brains of deceased AD individuals and cognitively impaired APP-PS1 mice, but not non-AD controls. These fragments potentially provide an inflammatory stimulus critical for neural tissue destruction and cognitive impairment. We tested whether vaccination against PNAG prevented microbial access to brains of APP-PS1 mice and impacted cognitive decline. Microbial factors were detected with a human IgG monoclonal antibody (MAb) to PNAG in brain tissues from human AD and APP/PS1 mice. Two cohorts of APP/PS1 mice and wild type (WT) littermate controls were vaccinated with either a PNAG vaccine (5GlcNH2 -TT) or TT (tetanus toxin) only as a control, five times starting at either 5 weeks or 5 months of age. Only PNAG-immunized mice made specific antibodies over the experimental period. Water T maze testing of mice was performed at 12-15 months of age. Brains were harvested to detect both PNAG and amyloid-ß immunohistochemically. PNAG-positive microbial factors were elevated in areas with amyloid-ß deposits in brain tissue from human AD cases and APP/PS1 mice. Non-AD age- and sex-matched controls had little detectable brain PNAG, even around amyloid-ß deposits. Active PNAG vaccination at both 5 weeks and 5 months of age prevented cognitive decline in APP-PS1 mice. Only 10% or 30% of non-immune APP/PS1 mice reached criteria by day 5 of reversal, respectively, compared to 90% and 100% of PNAG vaccinated APP/PS1 mice. Immunohistochemistry indicated decreased presence of PNAG-positive material in PNAG vaccinated mice and a modest reduction in amyloid-ß deposits. Antibodies to PNAG induced at 5 weeks or 5 months of age prevented cognitive decline and brain pathology in APP/PS1 mice, suggesting that microbial factors that enter the brain are critical for cognitive decline that may be prevented by vaccination.