The online version of this article (doi:10.1186/s12974-017-0826-5) contains supplementary material, which is available to authorized users.
Infection is a recognised risk factor for Alzheimer’s disease (AD) and can worsen symptoms in established disease. AD patients have higher rates of infection and are more likely to require hospital admissions due to infections than individuals without dementia. Infections have also been found to increase the risk of those over 84 years of age being diagnosed with dementia. However, few studies have investigated immune responses to infection in AD.
Here, we investigated the immune responses of the triple transgenic Alzheimer’s disease (3xTg-AD) mouse model of AD to infection with the parasites Toxoplasma gondii and Trichuris muris. Cytometric bead array, histology, immunohistochemistry and immunofluorescence were used to evaluate immune responses and the effects on the brain of acute infection.
3xTg-AD mice, despite having comparable parasite loads, were more susceptible to infection with more severe morbidity. A worsened outcome to infection can be linked to an exaggerated immune response. 3xTg-AD mice had an increased pro-inflammatory response characterised by the production of pro-inflammatory mediators such as tumour necrosis TNF-α, IL-6, CCL5 and CXCL-1, as well as an increase in immune cell infiltration to the sites of infection. T cell responses to parasite antigen also showed elevated production of the pro-inflammatory cytokines TNF-α (10 fold) and IL-6 (twofold). We investigated whether 3xTg-AD mice had a propensity for a more Th1-dominated response using the T. muris worm infection and showed that akin to T. gondii, there was an enhanced pro-inflammatory response which was associated with retention of worms in the gut and associated pathology. Irrespective of whether the infection was one that could infect the brain or cause a local gut inflammation, 3xTg-AD mice had increased numbers of activated microglia during infection in both the cortex and the hippocampus.
Our findings suggest that in AD, responses to infection are exaggerated outside of the CNS. Additionally, the results presented here indicate that both systemic and localised inflammation caused by an infection exacerbate neuroinflammation in AD.
Additional file 1: Figure S1. 11-month-old mice were infected with 1 × 104 tachyzoites of the PRU strain of T. gondii by oral gavage and culled at day 9 PI. One hemisphere of the brain was homogenised, RNA extracted and qPCR carried out for SAG-1 (tachyzoites) and Cysts. Data analysed by two-way ANOVA with Tukey’s multiple comparisons test. All data are shown as mean ± SEM. (TIF 17 kb)12974_2017_826_MOESM1_ESM.tif
Additional file 2: Figure S2. Cytokine levels in the brain at day 9 PI with T. gondii in 3xTg-AD mice. Mice were infected with 1 × 104 tachyzoites of T. gondii by oral gavage. One hemisphere of the brain was homogenised, RNA extracted and qPCR carried out on (A) 5–6-month-old and (B) 11–12-month-old animals. Data analysed by two-way ANOVA with Tukey’s multiple comparison test. All data are shown as mean ± SEM. (TIF 101 kb)12974_2017_826_MOESM2_ESM.tif
Additional file 3: Figure S3. 10-month-old 3xTg-AD mice were infected with 1 × 104 tachyzoites of T. gondii by IP injection. Open field behavioural testing was carried out 6 days PI. During open field, the (A) number of line crossings, (B) time spent mobile, (C) number of rears and (D) number of defecations during the test were measured. The Y-maze behavioural test was carried out 5 days PI. (E) Percentage alternations and (F) the number of arm entries in the Y-maze were measured. Data analysed by two-way ANOVA with Tukey’s multiple comparisons test, *p < 0.05; **p < 0.01. All data are shown as mean ± SEM. (TIF 133 kb)12974_2017_826_MOESM3_ESM.tif
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- Enhanced susceptibility of triple transgenic Alzheimer’s disease (3xTg-AD) mice to acute infection
Kathryn Jane Else
Sheena Margaret Cruickshank
Stuart McRae Allan
- BioMed Central