The Effect of Systemic Inflammation on the Accumulation and Spread of Tau Pathology.

Abstract

Alzheimer’s disease (AD) is a secondary tauopathy categorised by the presence of insoluble amyloid plaques and neurofibrillary tangles. Neurofibrillary tangles consist of hyperphosphorylated and misfolded tau protein. The pathological form of tau spreads through the limbic circuit and to the wider neocortex as the disease progresses. The spreading of aggregated tau throughout the brain in AD has long been associated with cognitive decline. These observations in AD patients have prompted further investigation behind this mechanism. It is hypothesised that the primary immune cell within the brain, microglia may be facilitating the spread of tau. In AD patients, systemic inflammatory episodes have been shown to correlate with an increase in cognitive decline. Therefore, peripheral inflammation may induce an inflammatory response within the brain and in turn promote the spread of tau pathology. This thesis aims to mimic the spreading of tau and observe the effect of systemic infection in vivo.

In this thesis, a tau spreading model was generated using C57BL/6 mice and H1Mapt-/- mice, a mouse which expresses all six isoforms of human tau with no disease-associated mutation. Mice received a unilateral injection of lysate enriched for Sarkosyl-insoluble tau derived from AD post-mortem tissue. Two months post-injection, mice received an intraperitoneal injection of either saline or Salmonella enterica serovar Typhimurium. S. typhimurium is a gram-negative bacterial strain which induces prolonged upregulation of pro-inflammatory cytokines, changes in microglial markers and splenomegaly, all of which are observed up to four weeks post-infection. Extensive histology was carried out in C57BL/6 and H1Mapt-/- mice to observe AT8-positive tau in distinct brain regions and examine the effect of systemic infection on tau burden. This infection was first established in the C57BL/6 and H1Mapt-/- mice without the spreading model to assess the baseline response to infection.

This thesis demonstrates propagation of tau pathology to regions within the limbic circuit connected synaptically. It was observed that systemic infection increases the rate of spread of AT8-positive tau through the brain. In regions within the limbic circuit, such as the mammillary nuclei, a significant increase in AT8-positive tau was observed after systemic infection. Markers of cellular and microglial activation MHCII and FcγRI, demonstrate a potential effect of ‘priming’ whereby the presence of tau pathology induces an exaggerated microglial response following systemic infection. MHCII also highlights a potential role of the vasculature. Differences were observed between the C57BL/6 and H1Mapt-/- mice both in tau burden and microglial response, supporting the role of systemic infection in the spatiotemporal spread of tau. The work described in this thesis demonstrates that systemic infection increases the spreading of tau pathology and prompts further study to investigate this mechanism further.

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Identifiers

ORCID for Jessica Teeling: orcid.org/0000-0003-4004-7391

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