Peripheral immune system and neuroimmune communication impairment in a mouse model of Alzheimer's disease

Giménez-Llort, Lydia; Maté, Ianire; Manassra, Rashed; Vida, Carmen; Fuente, Mónica De la

doi:10.1111/j.1749-6632.2012.06639.x

Cited by 48 publications

(51 citation statements)

References 80 publications

(294 reference statements)

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“…We did observe sporadic neurons positive for AT8, but no systematic differences with age or geno-type were observed, suggesting this signal was not disease-dependent. The current lack in neuropathology is consistent with delayed disease progression in males [64], relatively mild AD-like neuropathology at 12 months [31], and appearance of extracellular Aβ 1-42 plaques after 15 months of age [65]. Taken together, the neuropathological data suggested a shift to later ages in this mouse line.…”

Section: Discussionsupporting

confidence: 71%

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

Marchese

Cowan

Head

et al. 2014

JAD

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Background Immune system activation is frequently reported in patients with Alzheimer's disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration. Objective The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology. Methods A broad battery of tests was employed to assess behavioral performance and autoimmune/inflammatory markers in 3xTg-AD (AD) mice and wild type controls from 1.5 to 12 months of age. Results Aged AD mice displayed severe manifestations of systemic autoimmune/inflammatory disease, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired “cognitive” flexibility in the first 6 months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at an older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-β or tau pathology. Conclusion The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior. Consequently, 3xTg-AD mice may be a useful model in elucidating the role of immune system in the etiology of AD.

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Section: Discussionsupporting

confidence: 71%

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

Marchese

Cowan

Head

et al. 2014

JAD

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“…Consistent with our findings, previous work has found several differences in the immune systems of 3xTg-AD mice compared to Non-Tg animals. Naïve 3xTg-AD mice have been previously shown to have abnormal enlargement of the spleen and liver, an increased number of double-negative CD4 − CD8 − splenocytes [20], increased lymphocyte chemotaxis [21] and increased C-C chemokine receptor 6 (CCR6) expression outside of the CNS [22]. It is not clear how altered immune responses to infection outside of the CNS in AD mice relate to immune responses in AD patients although differences in the immune system are known to occur in AD patients.…”

Section: Discussionmentioning

confidence: 99%

“…Following lipopolysaccharide (LPS) stimulation of whole blood culture, AD patients had higher levels of IL-1β, TNF-α, IL-6 and IL-10 [11]. Dysregulation of the immune system has also been reported in the triple transgenic Alzheimer’s disease (3xTg-AD) mouse model of AD [20], including increased lymphocyte chemotaxis [21] and increased C-C chemokine receptor 6 (CCR6) expression outside of the CNS [22]. Additionally, functions of the immune system deteriorate with age, which is referred to as immunosenescence.…”

Section: Introductionmentioning

confidence: 99%

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

Rebecca

Kerry

Forman

et al. 2017

J Neuroinflammation

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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.

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“…Aging has been defined as a general and progressive impairment of the functions of the organism that lead to a lower ability to adaptively react to changes and preserve homeostasis [1]. Although the ethiopathogenesis of the different NDDs remains unclear, there is general consensus on the implication of common pathological mechanisms like oxidative stress, inflammation, mitochondrial dysfunction and protein misfolding.…”

Section: Introductionmentioning

confidence: 99%