Amyloid β-induced Mesenteric Inflammation in an Alzheimer’s Disease Transgenic Mouse Model

Author(s): Yasuhisa Ano*, Kumiko Ikado, Kazuyuki Uchida, Hiroyuki Nakayama.

Journal Name: Current Alzheimer Research

Volume 17 , Issue 1 , 2020

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Abstract:

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder histopathologically characterized by the accumulation of amyloid β (Aβ) peptides and inflammation associated with activated microglia. These features are well investigated in the central nervous system using AD-model mice; however, peripheral inflammation in these mice has not been investigated well.

Objective: We evaluated the inflammatory responses, especially myeloid dendritic cells (mDCs), in peripheral lymphoid tissues in AD-model mice to determine their association with Aβ deposition.

Methods: We collected lymphocytes from mesenteric lymphoid nodes (MLNs) and Peyer’s patches (PPs) of 5×FAD transgenic mice used as an AD model. Lymphocytes were analyzed using a flow cytometer to characterize mDCs and T cells. Collected lymphocytes were treated with Aβ1-42 ex vivo to evaluate the inflammatory response.

Results: We observed elevated levels of inflammatory cytokines and chemokines including interleukin (IL)-12 and macrophage inflammatory protein-1α in mDCs from MLNs and PPs and reduced levels of programmed death-ligand-1, an immunosuppressive co-stimulatory molecule, on the surface of mDCs from 5×FAD mice. Additionally, we found increases in interferon (IFN)-γ-producing CD4- or CD8- positive T cells in MLNs were increased in 5×FAD mice. Moreover, ex vivo treatment with Aβ peptides increased the production of IL-12 and IFN-γ by lymphocytes from 5×FAD mice.

Conclusion: The present study showed that pro-inflammatory mDC and T cells were induced in MLNs and PPs of 5×FAD mice.

Keywords: Alzheimer's disease, amyloid β, mesenteric lymphoid node, myeloid dendritic cells, Peyer’s patch, T cells.

[1]
Murphy MP, LeVine H III. Alzheimer’s disease and the amyloid-beta peptide. J Alzheimers Dis 19(1): 311-23. (2010).
[http://dx.doi.org/10.3233/JAD-2010-1221] [PMID: 20061647]
[2]
Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J. Amyloid-beta: a crucial factor in Alzheimer’s disease. Med Prin Prac Intern J Kuwait Unive. Health Sci Cent 24(1): 1-10. (2015).
[3]
O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34: 185-204. (2011).
[http://dx.doi.org/10.1146/annurev-neuro-061010-113613] [PMID: 21456963]
[4]
Wilkins HM, Swerdlow RH. Amyloid precursor protein processing and bioenergetics. Brain Res Bull 133: 71-9. (2017).
[http://dx.doi.org/10.1016/j.brainresbull.2016.08.009] [PMID: 27545490]
[5]
Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol 217(2): 459-72. (2018).
[http://dx.doi.org/10.1083/jcb.201709069] [PMID: 29196460]
[6]
Navarro V, Sanchez-Mejias E, Jimenez S, Munoz-Castro C, Sanchez-Varo R, Davila JC, et al. Microglia in Alzheimer’s disease: activated, dysfunctional or degenerative. Front Aging Neurosci 10: 140. (2018).
[http://dx.doi.org/10.3389/fnagi.2018.00140] [PMID: 29867449]
[7]
Sarlus H, Heneka MT. Microglia in Alzheimer’s disease. J Clin Invest 127(9): 3240-9. (2017).
[http://dx.doi.org/10.1172/JCI90606] [PMID: 28862638]
[8]
Mandrekar-Colucci S, Landreth GE. Microglia and inflammation in Alzheimer’s disease. CNS Neurol Disord Drug Targets 9(2): 156-67. (2010).
[http://dx.doi.org/10.2174/187152710791012071] [PMID: 20205644]
[9]
Varvel NH, Neher JJ, Bosch A, Wang W, Ransohoff RM, Miller RJ, et al. Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus. Proc Natl Acad Sci USA 113(38): E5665-74. (2016).
[http://dx.doi.org/10.1073/pnas.1604263113] [PMID: 27601660]
[10]
De Luigi A, Pizzimenti S, Quadri P, Lucca U, Tettamanti M, Fragiacomo C, et al. Peripheral inflammatory response in Alzheimer’s disease and multiinfarct dementia. Neurobiol Dis 11(2): 308-14. (2002).
[http://dx.doi.org/10.1006/nbdi.2002.0556] [PMID: 12505423]
[11]
O’Banion MK. Does peripheral inflammation contribute to Alzheimer disease? Evidence from animal models. Neurology 83(6): 480-1. (2014).
[http://dx.doi.org/10.1212/WNL.0000000000000663] [PMID: 24991028]
[12]
Surendranathan A, Su L, Mak E, Passamonti L, Hong YT, Arnold R, et al. Early microglial activation and peripheral inflammation in dementia with Lewy bodies. Brain 141(12): 3415-27. (2018).
[http://dx.doi.org/10.1093/brain/awy265] [PMID: 30403785]
[13]
Puig KL, Lutz BM, Urquhart SA, Rebel AA, Zhou X, Manocha GD, et al. Overexpression of mutant amyloid-β protein precursor and presenilin 1 modulates enteric nervous system. J Alzheimers Dis 44(4): 1263-78. (2015).
[http://dx.doi.org/10.3233/JAD-142259] [PMID: 25408221]
[14]
Semar S, Klotz M, Letiembre M, Van Ginneken C, Braun A, Jost V, et al. Changes of the enteric nervous system in amyloid-β protein precursor transgenic mice correlate with disease progression. J Alzheimers Dis 36(1): 7-20. (2013).
[http://dx.doi.org/10.3233/JAD-120511] [PMID: 23531500]
[15]
Puig KL, Swigost AJ, Zhou X, Sens MA, Combs CK. Amyloid precursor protein expression modulates intestine immune phenotype. J Neuroimmune Pharmacol J Soc NeuroImmune Pharmacol 7(1): 215-30. (2012).
[http://dx.doi.org/10.1007/s11481-011-9327-y]
[16]
Dansokho C, Ait Ahmed D, Aid S, Toly-Ndour C, Chaigneau T, Calle V, et al. Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain 139(Pt 4): 1237-51. (2016).
[http://dx.doi.org/10.1093/brain/awv408] [PMID: 26912648]
[17]
Jiang C, Li G, Huang P, Liu Z, Zhao B. The gut microbiota and Alzheimer’s disease. J Alzheimers Dis 58(1): 1-15. (2017).
[http://dx.doi.org/10.3233/JAD-161141] [PMID: 28372330]
[18]
Liu L, Zhu G. Gut-brain axis and mood disorder. Front Psychiatry 9: 223. (2018).
[http://dx.doi.org/10.3389/fpsyt.2018.00223] [PMID: 29896129]
[19]
Oakley H, Cole SL, Logan S, Erika Maus, Pei Shao, Jeffery Craft, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26(40): 10129-40. (2006).
[http://dx.doi.org/10.1523/JNEUROSCI.1202-06.2006] [PMID: 17021169]
[20]
Ano Y, Ikado K, Shindo K, Koizumi H, Fujiwara D. Identification of 14-dehydroergosterol as a novel anti-inflammatory compound inducing tolerogenic dendritic cells. Sci Rep 7(1): 13903. (2017).
[http://dx.doi.org/10.1038/s41598-017-14446-1] [PMID: 29066789]
[21]
Jounai K, Ikado K, Sugimura T, Ano Y, Braun J, Fujiwara D. Spherical lactic acid bacteria activate plasmacytoid dendritic cells immunomodulatory function via TLR9-dependent crosstalk with myeloid dendritic cells. PLoS One 7(4) e32588 (2012).
[http://dx.doi.org/10.1371/journal.pone.0032588] [PMID: 22505996]
[22]
Ano Y, Ozawa M, Kutsukake T, Sugiyama S, Uchida KA, Yoshida A, et al. Preventive effects of a fermented dairy product against Alzheimer’s disease and identification of a novel oleamide with enhanced microglial phagocytosis and anti-inflammatory activity. PLoS One 10(3) e0118512 (2015).
[http://dx.doi.org/10.1371/journal.pone.0118512] [PMID: 25760987]
[23]
Ano Y, Dohata A, Taniguchi Y, Hoshi A, Uchida K, Takashima A, et al. Iso-α-acids, bitter components of beer, prevent inflammation and cognitive decline induced in a mouse model of Alzheimer’s disease. J Biol Chem 292(9): 3720-8. (2017).
[http://dx.doi.org/10.1074/jbc.M116.763813] [PMID: 28087694]
[24]
Ciaramella A, Sanarico N, Bizzoni F, Moro ML, Salani F, Scapigliati G, et al. Amyloid beta peptide promotes differentiation of pro-inflammatory human myeloid dendritic cells. Neurobiol Aging 2009; 30(2): 210-21.
[http://dx.doi.org/10.1016/j.neurobiolaging.2007.06.007] [PMID: 17658667]
[25]
Bossù P, Spalletta G, Caltagirone C, Ciaramella A. Myeloid dendritic cells are potential players in human neurodegenerative Diseases. Front Immunol 6: 632. (2015).
[http://dx.doi.org/10.3389/fimmu.2015.00632] [PMID: 26734003]
[26]
Laurent C, Dorothée G, Hunot S, Martin E, Monnet Y, Duchamp M, et al. Hippocampal T cell infiltration promotes neuroinflam-mation and cognitive decline in a mouse model of tauopathy. Brain 140(1): 184-200. (2017).
[http://dx.doi.org/10.1093/brain/aww270] [PMID: 27818384]
[27]
Browne TC, McQuillan K, McManus RM, O'Reilly JA, Mills KH, Lynch MA. IFN-gamma Production by amyloid beta-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. J Immunool (Baltimore, Md : 1950) 190(5): 2241-51. (2013).
[28]
Baek H, Ye M, Kang GH, Lee C, Lee G, Choi DA, et al. Neuroprotective effects of CD4+CD25+Foxp3+ regulatory T cells in a 3xTg-AD Alzheimer’s disease model. Oncotarget 7(43): 69347-57. (2016).
[http://dx.doi.org/10.18632/oncotarget.12469] [PMID: ]27713140]
[29]
Tanaka H, Demeure CE, Rubio M, Delespesse G, Sarfati M. Human monocyte-derived dendritic cells induce naive T cell differentiation into T helper cell type 2 (Th2) or Th1/Th2 effectors. Role of stimulator/responder ratio. J Exp Med 192(3): 405-12. (2000).
[http://dx.doi.org/10.1084/jem.192.3.405] [PMID: 10934228]
[30]
Vieira PL, de Jong EC, Wierenga EA, Kapsenberg ML, Kalinski P. Development of Th1-inducing capacity in myeloid dendritic cellsrequires environmental instruction. J Immunol (Baltimore, Md : 1950) 164(9): 4507-12. (2000).
[http://dx.doi.org/10.4049/jimmunol.164.9.4507]
[31]
Kushwah R, Hu J. Role of dendritic cells in the induction of regulatory T cells. Cell Biosci 1(1): 20. (2011).
[http://dx.doi.org/10.1186/2045-3701-1-20] [PMID: 21711933]
[32]
Lichtenegger FS, Mueller K, Otte B, Beck B, Hiddemann W, Schendel DJ, et al. CD86 and IL-12p70 are key players for T helper 1 polarization and natural killer cell activation by Toll-like receptor-induced dendritic cells. PLoS One 7(9) e44266 (2012).
[http://dx.doi.org/10.1371/journal.pone.0044266] [PMID: 22962607]
[33]
Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1(9): 793-801. (1994).
[http://dx.doi.org/10.1016/S1074-7613(94)80021-9] [PMID: 7534620]
[34]
Dai S, Jia R, Zhang X, Fang Q, Huang L. The PD-1/PD-Ls pathway and autoimmune diseases. Cell Immunol 290(1): 72-9. (2014).
[http://dx.doi.org/10.1016/j.cellimm.2014.05.006] [PMID: 24908630]
[35]
Collins AV, Brodie DW, Gilbert RJ, Iaboni A, Manso-Sancho R, Walse B, et al. The interaction properties of costimulatory molecules revisited. Immunity 17(2): 201-10. (2002).
[http://dx.doi.org/10.1016/S1074-7613(02)00362-X] [PMID: 12196291]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 17
ISSUE: 1
Year: 2020
Page: [52 - 59]
Pages: 8
DOI: 10.2174/1567205017666200212160343
Price: $65

Article Metrics

PDF: 10
HTML: 4
EPUB: 2
PRC: 1