title: Enhanced susceptibility of triple transgenic Alzheimer's disease (3xTg-AD) mice to acute infection.
abstract: 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.
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Montacute
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Kerry
authors.initials: K
authors.lastname: Foley
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Forman
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Kathryn Jane
authors.initials: KJ
authors.lastname: Else
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK. Sheena.Cruickshank@manchester.ac.uk.
authors.forename: Sheena Margaret
authors.initials: SM
authors.lastname: Cruickshank
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Stuart McRae
authors.initials: SM
authors.lastname: Allan
mesh_terms: D000208:Acute Disease; D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D004198:Disease Susceptibility / Q000276:immunology* / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014257:Trichuriasis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
keywords: Alzheimer’s disease; Cytokines; Infection; Inflammation; Microglia; Neuroinflammation; Toxoplasma gondii; Trichuris muris