Examining the role of systemic inflammation in Alzheimer’s disease using in vivo models of tauopathy.

Identification: Howard, Sarah


Description

Examining the role of systemic inflammation in Alzheimer's disease using in vivo models of tauopathy
 
Sarah Howard1, Mariana Vargas-Caballero1, Zeshan Ahmed2, Katrin Deinhardt1 and Jessica L. Teeling1
1
Biological Sciences, University of Southampton, Southampton, UK; 2.Eli Lilly, Surrey, UK

 
Introduction: Acute systemic inflammation in patients with Alzheimer's disease (AD) has been associated with an exacerbation in cognitive decline. In AD, intraneuronal hyperphosphorylated tau is believed to spread through the brain via trans-synaptic prion-like propagation; however, the precise mechanisms that control spatiotemporal spread of tau are unknown. Evidence suggests that tau spread can be altered by microglial activation and stress granule function, proposing a role for immune responses in the brain. Here we aim to investigate the effect of a low-grade systemic bacterial infection in transgenic models of tauopathy.
Methods: Historically, lipopolysaccharide (LPS) has been used to mimic systemic bacterial infections both in vivo and in vitro. Unlike real infections, this response is relatively short lived, so we aimed to establish a more representative model of systemic infection by using a live, non-neurotrophic bacterial strain of Salmonella Typhimurium. We used a range of experimental tauopathy models (P301S, Mapt-/- and hTau) and wild type C57BL/6.  Body and spleen weight was measured to determine susceptibility to infection and brain tissue was collected 4 weeks post infection to assess neuroinflammation markers.
Results: We observed differential susceptibility to Salmonella Typhimurium infection in tauopathy models. The difference observed between the models is most likely due to polymorphisms within the NRAMP1 gene, a lysosomal membrane protein expressed in monocytes and macrophages and associated with iron availability. Genetic lines that responded to the bacterial infection showed increased spleen size, cerebral endothelial cell activation and microglial phenotype changes 4 weeks post infection. These observations suggest prolonged neuroinflammation in response to a low-grade systemic infection.
Conclusion: Variability in genetic lines of in vivo tauopathy models appears to alter the response to systemic infection. We have established that hTau mice are susceptible to Salmonella Typhimurium infection, which will allow further investigation into the role of systemic inflammation on tau pathogenesis in vivo.
 

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