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Cited by 43Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsImmunotoxicology and immune responses

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

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Montacute, Rebecca, Foley, Kerry, Forman, Ruth, Else, Kathryn Jane, Cruickshank, Sheena Margaret, Allan, Stuart McRae·2017·Journal of Neuroinflammation
DOI 10.1186/s12974-017-0826-5PMC PMC5346250
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Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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  1. [1]Querfurth HW LaFerla FM Alzheimer’s disease N Engl J Med 2010 362 329 344 10.1056/NEJMra0909142 20107219 · DOI · Paper page
  2. [2]Isik AT Late onset Alzheimer’s disease in older people Clin Interv Aging 2010 5 307 311 10.2147/CIA.S11718 21103401 PMC2981103 · DOI
  3. [3]Carter MW Porell FW Vulnerable populations at risk of potentially avoidable hospitalizations: the case of nursing home residents with Alzheimer’s disease Am J Alzheimers Dis Other Demen 2005 20 349 358 10.1177/153331750502000605 16396440 PMC10833338 · DOI
  4. [4]Heun R Schoepf D Potluri R Natalwala A Alzheimer’s disease and co-morbidity: increased prevalence and possible risk factors of excess mortality in a naturalistic 7-year follow-up Eur Psychiatry 2013 28 40 48 10.1016/j.eurpsy.2011.06.001 21924588 · DOI
  5. [5]Natalwala A Potluri R Uppal H Heun R Reasons for hospital admissions in dementia patients in Birmingham, UK, during 2002–2007 Dement Geriatr Cogn Disord 2008 26 499 505 10.1159/000171044 19005254 · DOI
  6. [6]Brunnström HR Englund EM Cause of death in patients with dementia disorders Eur J Neurol 2009 16 488 492 10.1111/j.1468-1331.2008.02503.x 19170740 · DOI · Paper page
  7. [7]Dunn N Mullee M Perry VH Holmes C Ovid: Association between dementia and infectious disease: evidence from a case–control study Alzheimer Dis Assoc Disord 2005 19 91 94 10.1097/01.wad.0000165511.52746.1f 15942327 · DOI
  8. [9]Guerreiro R Wojtas A Bras J Carrasquillo M Rogaeva E Majounie E Cruchaga C Sassi C Kauwe JSK Younkin S Hazrati L Collinge J Pocock J Lashley T Williams J Lambert J-C Amouyel P Goate A Rademakers R Morgan K Powell J St George-Hyslop P Singleton A Hardy J TREM2 variants in Alzheimer’s disease N Engl J Med 2013 368 117 127 10.1056/NEJMoa1211851 23150934 PMC3631573 · DOI · Paper page
  9. [10]Lambert J-C Grenier-Boley B Chouraki V Heath S Zelenika D Fievet N Hannequin D Pasquier F Hanon O Brice A Epelbaum J Berr C Dartigues J-F Tzourio C Campion D Lathrop M Amouyel P Implication of the immune system in Alzheimer’s disease: evidence from genome-wide pathway analysis J Alzheimers Dis 2010 20 1107 1118 20413860
  10. [11]Lombardi VR García M Rey L Cacabelos R Characterization of cytokine production, screening of lymphocyte subset patterns and in vitro apoptosis in healthy and Alzheimer’s disease (AD) individuals J Neuroimmunol 1999 97 163 171 10.1016/S0165-5728(99)00046-6 10408971 · DOI
  11. [12]Bonotis K Krikki E Holeva V Aggouridaki C Costa V Baloyannis S Systemic immune aberrations in Alzheimer’s disease patients J Neuroimmunol 2008 193 183 187 10.1016/j.jneuroim.2007.10.020 18037502 · DOI
  12. [14]Hu GR Walls RS Creasey H McCusker E Broe GA Peripheral blood lymphocyte subset distribution and function in patients with Alzheimer’s disease and other dementias Aust N Z J Med 1995 25 212 217 10.1111/j.1445-5994.1995.tb01525.x 7487688 · DOI
  13. [16]Leffell MS Lumsden L Steiger WA An analysis of T lymphocyte subpopulations in patients with Alzheimer’s disease J Am Geriatr Soc 1985 33 4 8 10.1111/j.1532-5415.1985.tb02851.x 3155531 · DOI
  14. [17]Ikeda T Yamamoto K Takahashi K Yamada M Immune system-associated antigens on the surface of peripheral blood lymphocytes in patients with Alzheimer’s disease Acta Psychiatr Scand 1991 83 444 448 10.1111/j.1600-0447.1991.tb05573.x 1679280 · DOI
  15. [18]Licastro F Pedrini S Caputo L Annoni G Davis LJ Ferri C Casadei V Grimaldi LM Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or signals from the brain? J Neuroimmunol 2000 103 97 102 10.1016/S0165-5728(99)00226-X 10674995 · DOI
  16. [20]Marchese M Cowan D Head E Ma D Karimi K Ashthorpe V Kapadia M Zhao H Davis P Sakic B Autoimmune manifestations in the 3xTg-AD model of Alzheimer’s disease J Alzheimers Dis 2014 39 191 210 24150111 PMC4376359
  17. [21]Giménez-Llort L Maté I Manassra R Vida C De la Fuente M Peripheral immune system and neuroimmune communication impairment in a mouse model of Alzheimer’s disease Ann N Y Acad Sci 2012 1262 74 84 10.1111/j.1749-6632.2012.06639.x 22823438 · DOI
  18. [22]Subramanian S Ayala P Wadsworth TL Harris CJ Vandenbark AA Quinn JF Offner H CCR6: a biomarker for Alzheimer’s-like disease in a triple transgenic mouse model J Alzheimers Dis 2010 22 619 629 20847401 PMC2988888
  19. [23]Dorshkind K Montecino-Rodriguez E Signer RAJ The ageing immune system: is it ever too old to become young again? Nat Rev Immunol 2009 9 57 62 10.1038/nri2471 19104499 · DOI
  20. [24]Lemstra AW Groen in’t Woud JCM Hoozemans JJM van Haastert ES Rozemuller AJM Eikelenboom P van Gool WA Microglia activation in sepsis: a case–control study J Neuroinflammation 2007 4 4 10.1186/1742-2094-4-4 17224051 PMC1783646 · DOI
  21. [25]Semmler A Okulla T Sastre M Dumitrescu-Ozimek L Heneka MT Systemic inflammation induces apoptosis with variable vulnerability of different brain regions J Chem Neuroanat 2005 30 144 157 10.1016/j.jchemneu.2005.07.003 16122904 · DOI
  22. [26]Holmes C El-Okl M Williams AL Cunningham C Wilcockson D Perry VH Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer’s disease J Neurol Neurosurg Psychiatry 2003 74 788 789 10.1136/jnnp.74.6.788 12754353 PMC1738504 · DOI
  23. [28]Perry VH Holmes C Microglial priming in neurodegenerative disease Nat Rev Neurol 2014 10 217 224 10.1038/nrneurol.2014.38 24638131 · DOI · Paper page
  24. [29]Lyons RE McLeod R Roberts CW Toxoplasma gondii tachyzoite–bradyzoite interconversion Trends Parasitol 2002 18 198 201 10.1016/S1471-4922(02)02248-1 11983592 · DOI
  25. [30]Berenreiterová M Flegr J Kuběna AA Němec P The distribution of Toxoplasma gondii cysts in the brain of a mouse with latent toxoplasmosis: implications for the behavioral manipulation hypothesis PLoS One 2011 6 e28925 10.1371/journal.pone.0028925 22194951 PMC3237564 · DOI
  26. [31]Else KJ Finkelman FD Maliszewski CR Grencis RK Cytokine-mediated regulation of chronic intestinal helminth infection J Exp Med 1994 179 347 351 10.1084/jem.179.1.347 8270879 PMC2191309 · DOI
  27. [32]Jung BK Pyo KH Shin KY Hwang YS Lim H Lee SJ Moon JH Lee SH Suh YH Chai JY Shin EH Toxoplasma gondii infection in the brain inhibits neuronal degeneration and learning and memory impairments in a murine model of Alzheimer’s disease PLoS One 2012 7 e33312 10.1371/journal.pone.0033312 22470449 PMC3310043 · DOI
  28. [33]Möhle L Israel N Paarmann K Krohn M Pietkiewicz S Müller A Lavrik IN Buguliskis JS Schott BH Schlüter D Gundelfinger ED Montag D Seifert U Pahnke J Dunay IIR Reitz C Brayne C Mayeux R Hardy J Selkoe D Selkoe D Haass C Kaether C Thinakaran G Sisodia S Masters C Selkoe D Mawuenyega K Sigurdson W Ovod V Chronic Toxoplasma gondii infection enhances β-amyloid phagocytosis and clearance by recruited monocytes Acta Neuropathol Commun 2016 4 25 10.1186/s40478-016-0293-8 26984535 PMC4793516 · DOI
  29. [34]Schaeffer M Han S-J Chtanova T van Dooren GG Herzmark P Chen Y Roysam B Striepen B Robey EA Dynamic imaging of T cell-parasite interactions in the brains of mice chronically infected with Toxoplasma gondii J Immunol 2009 182 6379 6393 10.4049/jimmunol.0804307 19414791 · DOI
  30. [35]Wakelin D Acquired immunity to Trichuris muris in the albino laboratory mouse Parasitology 1967 57 515 524 10.1017/S0031182000072395 6048569 · DOI
  31. [36]Honjo K van Reekum R Verhoeff NPLG Alzheimer’s disease and infection: do infectious agents contribute to progression of Alzheimer’s disease? Alzheimers Dement 2009 5 348 360 10.1016/j.jalz.2008.12.001 19560105 · DOI
  32. [37]Foley NC Affoo RH Martin RE A systematic review and meta-analysis examining pneumonia-associated mortality in dementia Dement Geriatr Cogn Disord 2015 39 52 67 10.1159/000367783 25342272 · DOI
  33. [38]Cestari JAF, Fabri GMC, Kalil J, Nitrini R, Jacob-Filho W, de Siqueira JTT, Siqueira SRDT. Oral infections and cytokine levels in patients with Alzheimer’s disease and mild cognitive impairment compared with controls. J Alzheimers Dis. 2016;Preprint(Preprint):1–7.
  34. [42]Pappas G Roussos N Falagas ME Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis Int J Parasitol. 2009 39 1385 94 10.1016/j.ijpara.2009.04.003 19433092 · DOI
  35. [43]Kusbeci OY Miman O Yaman M Aktepe OC Yazar S Could Toxoplasma gondii have any role in Alzheimer disease? Alzheimer Dis Assoc Disord 2011 25 1 3 10.1097/WAD.0b013e3181f73bc2 20921875 · DOI

Cited by

Sorted by citations

Authors
Montacute, R., Foley, K., Forman, R., Else, K. J., Cruickshank, S. M., & Allan, S. M.
Affiliations
University of Manchester (GB)
Corresponding author
Cruickshank, Sheena Margaret
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2017-03-11
Volume
14
Issue
1
Pages
50-50
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-017-0826-5
PMC
PMC5346250
OpenAlex
W2592980662
Cited by
43
References
8
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 8 · 2021: 9 · 2020: 4 · 2019: 5 · 2018: 6 · 2017: 2
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, cc-by)
Funders
Medical Research Council
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords
Alzheimer's disease, 3xTg-AD mice, infection susceptibility, Toxoplasma gondii, Trichuris muris, neuroinflammation, inflammatory cytokines, Th1 response, microglial activation, immune cell infiltration, intestinal inflammation, T cell response, TNF-α, interleukin-6
MeSH terms
Acute Disease, Alzheimer Disease, Animals, Disease Susceptibility, Male, Mice, Inbred C57BL, Mice, Transgenic, Toxoplasmosis, Trichuriasis, Genetic Predisposition to Disease, Mice

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