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Title: The impact of systemic inflammation on neuroinflammation and tau phosphorylation in healthy ageing and pathology
Author: Collcutt, Alexander William
ISNI:       0000 0004 7234 1242
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2017
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Systemic infections accelerate the progression of neurodegenerative conditions, such as Alzheimer’s disease (AD), but reasons for this remain unclear. Previous studies utilising the bacterial mimetic lipopolysaccharide (LPS), suggest that systemic inflammation exacerbates and/or induces proinflammatory processes in the brain. In turn, this results in an imbalance in kinase and phosphatase activity with subsequent pathological hyperphosphorylation of tau - a key neuropathological hallmark of AD. However, these findings have not been corroborated with examples of common bacterial infections. To address this issue, adult (3-4 month old) wild-type mice were infected with an attenuated strain of the bacterium S. Typhimurium. The bacteria induced a diverse systemic and neuroinflammatory response up to 4 weeks post infection, with the elevation of proinflammatory cytokines such as IFN-γ, IL-1β and IL-6, and microglia phenotype changes including increased FcγRI expression. Cells associated with the cerebral vasculature expressed MHCII while there was evidence of IgG infiltration into the brain parenchyma. While microglial expression of FcyRI and CD11b expression increased following multiple systemic LPS challenges, this model displayed no alterations at the cerebral vasculature and an attenuated central immune response, with only modest elevations in IL-1β and mKC, suggesting the development of endotoxin tolerance. Nevertheless, neither systemic LPS challenge nor S. Typhimurium infection induced tau phosphorylation in adult wild-type mice. As age is the biggest risk factor for neurodegenerative disease, the effects of these two models of systemic inflammation were investigated in middle-age (11-12 month old) wild-type mice. While a similar peripheral and neuroinflammatory immune profile was observed in the middle-aged and adult mice, a trend suggested S. Typhimurium caused increased tau phosphorylation in middle-aged wild-type mice, 4 weeks post infection. As the opposite trend was observed following multiple LPS challenges, differences between the models, including S. Typhimurium-induced IgG infiltration, may be responsible. An additional pathological hallmark of AD is the deposition of Aβ protein. Using an aged (16-17 month old) transgenic mouse model that develops extensive Aβ plaque pathology (Tg2576), it was shown that the presence of these deposits induced tau phosphorylation. However, when infected with S. Typhimurium, only the aged non-transgenic mice displayed significantly increased tau phosphorylation with no additional effect observed in the Tg2576 mice. In conclusion, these studies suggest the ageing brain is vulnerable to the deleterious effects of systemic inflammation.
Supervisor: Teeling, Jessica Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available