Enhanced susceptibility of triple transgenic Alzheimer’s disease (3xTg-AD) mice to acute infection

Abstract

BackgroundInfection 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.MethodsHere, 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.Results3xTg-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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0826-5) contains supplementary material, which is available to authorized users.

Unravelling Alzheimer's Disease: It's Not the Whole Story, but Aβ Still Matters

“…Circumstantially, the construct fits with the epidemiologic associations of prior CNS infections as summarized by Itzhaki (33) (and others) and the observations that the defensin activity of Ab is enhanced by oligomerization (34). There are inconsistencies with at least one other study in older 3X transgenic mice, which do not show increased resistance to systemic infection (35). If the defensin notion turns out to be substantially correct, therapies that efficiently suppress Ab production or aggregation could put patients receiving such treatment at risk for CNS infection.…”

Acute effects of systemic inflammation upon neurovascular unit and cerebrovascular function.

“…This could explain why studies comparing brain and peripheral inflammatory challenges such as the one by Montacute etal. [60] report similar levels of brain inflammation in both challenges.…”

LatentToxoplasma gondiiinfection increases soluble mutant huntingtin and promotes neurodegeneration in the YAC128 mouse model of Huntington’s disease

“…Cytokines including IL--6 and TNFα, that are characteristic of neuroinflammation, reduce the clearance of misfolded proteins such as Aβ and tau [44, 78--80]. T. gondii infection, which also results in elevated IL--6 and TNFα, induces Aβ deposition and tau hyperphosphorylation that are associated with behavioral deficits in mice [25,38]. Interestingly, one mechanism by which T. gondii evades clearance is by inhibiting autophagy [81,82], and suppression of autophagy is sufficient to induce neurodegeneration [83,84].…”

“…Whereas the role of aseptic inflammation in HD and related protein--misfolding diseases has been well studied [26--28], how common latent brain infections, such as with T. gondii or HSV1, affect this and the underlying diseases is poorly understood. Interestingly, a transgenic mouse model of Alzheimer's disease has an enhanced inflammatory response to acute T. gondii infection [38]. We have previously studied T. gondii infection in N171--82Q HD mice and reported premature mortality compared to non--infected HD mice [39].…”