MURINE MODELS OF SYSTEMIC INFLAMMATION AND DEMENTIA: HOW ARE THEY CONNECTED?

Abstract

There is growing evidence for a role of systemic microbial infections in the onset and/or progression of a number of chronic neurodegenerative diseases including Alzheimer's disease (AD). While these observations further support a role of the immune system in the pathogenesis of AD, the underlying biological mechanisms by which systemic infections drive disease progression are incompletely understood. We have previously shown that a real-life systemic bacterial infection results in long-lasting changes to the blood brain barrier permeability, microglial activation and infiltration of lymphocytes into the brain of adult mice. In this study we explore the effect of systemic infection in experimental models of Alzheimer's Disease. Transgenic mice carrying hAPPswe were challenged with an attenuated bacterial strain of Salmonella typhimurium at different stages of disease (12, 16 and 20 months). Brain and serum samples were collected and analysed for amyloid load, neuroinflammation, and BBB permeability using immunohistochemistry and multiplex immune assays. Tg2576 mice showed increased amyloid load following systemic bacterial infection, regardless of the stage of the disease, whilst no amyloid was detected in wild type mice. Bacterial infection resulted in increased neuroinflammatory response in both wild type and Tg2576 mice, measured by microglial phenotype changes and pro-inflammatory cytokine levels, but this response was prolonged in Tg2576 mice, especially in 12 month old mice. Blood brain barrier permeability for plasma proteins was increased following bacterial infection in both wild type and Tg2576, but recruitment of lymphocytes was exaggerated in Tg2576. Our results suggest that environmental stimuli, such as systemic bacterial infections, will contribute to earlier onset and progression of neuropathology in the Tg2576 model of Alzheimer's disease. These observations may explain the exaggerated clinicial symptoms reported in AD patients who are exposed to systemic microbial infection.