Investigating the role of neuroinflammation on the accumulation and spread of tau pathology.

Many studies have investigated the effect of inflammation on amyloid pathology, yet its effect on the severity of tau pathology remains understudied. Tau is a microtubule associated protein which in AD becomes hyperphosphorylated and accumulates in neurons to form NFTs. Unlike amyloid plaques, the severity of NFT pathology in AD correlates with cognitive decline. In AD patients, NFT pathology progresses in a stereotypical pattern affecting the entorhinal cortex first, followed by the hippocampus and finally spreading to the neocortex. The progressive accumulation and spread of tau pathology has been replicated in animal models. We have shown that systemic inflammation, induced by intraperitoneal injection of LPS or real life bacteria (Salmonella typhimurium) accelerates ongoing CNS disease via activation of endothelial cells and microglia and a recent clinical study showed 5-fold faster decline in cognitive function when serum levels of pro-inflammatory cytokines are elevated after exposure to a systemic infection. These studies suggest that sustained low grade systemic inflammation is a major risk factor for earlier onset of disease.
In this collaborative study we aim to test the hypothesis that systemic inflammation accelerates the accumulation and spread of tau pathology thus contributing to disease pathogenesis.