Top

Published in:

Open Access 01-12-2023 | Alzheimer's Disease | Research

Inhibition of microfold cells ameliorates early pathological phenotypes by modulating microglial functions in Alzheimer’s disease mouse model

Authors: Namkwon Kim, In Gyoung Ju, Seung Ho Jeon, Yeongae Lee, Min-Ji Jung, Min Sung Gee, Jae Seok Cho, Kyung-Soo Inn, Lee Ann Garrett-Sinha, Myung Sook Oh, Jong Kil Lee

Published in: Journal of Neuroinflammation | Issue 1/2023

Abstract

Background

The gut microbiota has recently attracted attention as a pathogenic factor in Alzheimer’s disease (AD). Microfold (M) cells, which play a crucial role in the gut immune response against external antigens, are also exploited for the entry of pathogenic bacteria and proteins into the body. However, whether changes in M cells can affect the gut environments and consequently change brain pathologies in AD remains unknown.

Methods

Five familial AD (5xFAD) and 5xFAD-derived fecal microbiota transplanted (5xFAD-FMT) naïve mice were used to investigate the changes of M cells in the AD environment. Next, to establish the effect of M cell depletion on AD environments, 5xFAD mice and Spib knockout mice were bred, and behavioral and histological analyses were performed when M cell-depleted 5xFAD mice were six or nine months of age.

Results

In this study, we found that M cell numbers were increased in the colons of 5xFAD and 5xFAD-FMT mice compared to those of wild-type (WT) and WT-FMT mice. Moreover, the level of total bacteria infiltrating the colons increased in the AD-mimicked mice. The levels of M cell-related genes and that of infiltrating bacteria showed a significant correlation. The genetic inhibition of M cells (Spib knockout) in 5xFAD mice changed the composition of the gut microbiota, along with decreasing proinflammatory cytokine levels in the colons. M cell depletion ameliorated AD symptoms including amyloid-β accumulation, microglial dysfunction, neuroinflammation, and memory impairment. Similarly, 5xFAD-FMT did not induce AD-like pathologies, such as memory impairment and excessive neuroinflammation in Spib^−/− mice.

Conclusion

Therefore, our findings provide evidence that the inhibiting M cells can prevent AD progression, with therapeutic implications.

Available only for authorised users

Bloom GS. Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014;71(4):505–8. https://doi.org/10.1001/jamaneurol.2013.5847. (PubMed PMID: 24493463).CrossRefPubMed

Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17(3):157–72. https://doi.org/10.1038/s41582-020-00435-y.CrossRefPubMed

Ma Q, Xing C, Long W, Wang HY, Liu Q, Wang RF. Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis. J Neuroinflammation. 2019;16(1):53. https://doi.org/10.1186/s12974-019-1434-3.CrossRefPubMedPubMedCentral

Gomborone JE, Dewsnap PA, Libby GW, Farthing MJ. Selective affective biasing in recognition memory in the irritable bowel syndrome. Gut. 1993;34(9):1230–3. https://doi.org/10.1136/gut.34.9.1230.CrossRefPubMedPubMedCentral

De Palma G, Lynch MD, Lu J, Dang VT, Deng Y, Jury J, et al. Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice. Sci Transl Med. 2017. https://doi.org/10.1126/scitranslmed.aaf6397.CrossRefPubMed

Zonis S, Pechnick RN, Ljubimov VA, Mahgerefteh M, Wawrowsky K, Michelsen KS, et al. Chronic intestinal inflammation alters hippocampal neurogenesis. J Neuroinflammation. 2015;12:65. https://doi.org/10.1186/s12974-015-0281-0.CrossRefPubMedPubMedCentral

Kim N, Jeon SH, Ju IG, Gee MS, Do J, Oh MS, et al. Transplantation of gut microbiota derived from Alzheimer’s disease mouse model impairs memory function and neurogenesis in C57BL/6 mice. Brain Behav Immun. 2021;98:357–65. https://doi.org/10.1016/j.bbi.2021.09.002.CrossRefPubMed

Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100(23):13632–7. https://doi.org/10.1073/pnas.2234031100.CrossRefPubMedPubMedCentral

Jang SE, Lim SM, Jeong JJ, Jang HM, Lee HJ, Han MJ, et al. Gastrointestinal inflammation by gut microbiota disturbance induces memory impairment in mice. Mucosal Immunol. 2018;11(2):369–79. https://doi.org/10.1038/mi.2017.49.CrossRefPubMed

10.

Chen C, Ahn EH, Kang SS, Liu X, Alam A, Ye K. Gut dysbiosis contributes to amyloid pathology, associated with C/EBPbeta/AEP signaling activation in Alzheimer’s disease mouse model. Sci Adv. 2020;6(31):eaba0466. https://doi.org/10.1126/sciadv.aba0466.CrossRefPubMedPubMedCentral

11.

Mezo C, Dokalis N, Mossad O, Staszewski O, Neuber J, Yilmaz B, et al. Different effects of constitutive and induced microbiota modulation on microglia in a mouse model of Alzheimer’s disease. Acta Neuropathol Commun. 2020;8(1):119. https://doi.org/10.1186/s40478-020-00988-5.CrossRefPubMedPubMedCentral

12.

Albac S, Schmitz A, Lopez-Alayon C, d’Enfert C, Sautour M, Ducreux A, et al. Candida albicans is able to use M cells as a portal of entry across the intestinal barrier in vitro. Cell Microbiol. 2016;18(2):195–210. https://doi.org/10.1111/cmi.12495.CrossRefPubMed

13.

Martinez-Argudo I, Sands C, Jepson MA. Translocation of enteropathogenic Escherichia coli across an in vitro M cell model is regulated by its type III secretion system. Cell Microbiol. 2007;9(6):1538–46. https://doi.org/10.1111/j.1462-5822.2007.00891.x.CrossRefPubMed

14.

Donaldson DS, Kobayashi A, Ohno H, Yagita H, Williams IR, Mabbott NA. M cell-depletion blocks oral prion disease pathogenesis. Mucosal Immunol. 2012;5(2):216–25. https://doi.org/10.1038/mi.2011.68.CrossRefPubMedPubMedCentral

15.

Tahoun A, Mahajan S, Paxton E, Malterer G, Donaldson DS, Wang D, et al. Salmonella transforms follicle-associated epithelial cells into M cells to promote intestinal invasion. Cell Host Microbe. 2012;12(5):645–56. https://doi.org/10.1016/j.chom.2012.10.009.CrossRefPubMed

16.

Bennett KM, Parnell EA, Sanscartier C, Parks S, Chen G, Nair MG, et al. Induction of Colonic M Cells during Intestinal Inflammation. Am J Pathol. 2016;186(5):1166–79. https://doi.org/10.1016/j.ajpath.2015.12.015.CrossRefPubMedPubMedCentral

17.

Lee JY, Han SH, Park MH, Song IS, Choi MK, Yu E, et al. N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer’s disease. Nat Commun. 2020;11(1):2358. https://doi.org/10.1038/s41467-020-16080-4.CrossRefPubMedPubMedCentral

18.

Smillie CS, Biton M, Ordovas-Montanes J, Sullivan KM, Burgin G, Graham DB, et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell. 2019;178(3):714-30.e22. https://doi.org/10.1016/j.cell.2019.06.029.CrossRefPubMedPubMedCentral

19.

Nair VR, Franco LH, Zacharia VM, Khan HS, Stamm CE, You W, et al. Microfold cells actively translocate mycobacterium tuberculosis to initiate infection. Cell Rep. 2016;16(5):1253–8. https://doi.org/10.1016/j.celrep.2016.06.080.CrossRefPubMedPubMedCentral

20.

Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation. 2008;5:37. https://doi.org/10.1186/1742-2094-5-37.CrossRefPubMedPubMedCentral

21.

Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med. 2017;23(9):1018–27. https://doi.org/10.1038/nm.4397.CrossRefPubMed

22.

Agirman G, Yu KB, Hsiao EY. Signaling inflammation across the gut-brain axis. Science. 2021;374(6571):1087–92. https://doi.org/10.1126/science.abi6087.CrossRefPubMed

23.

Town T, Tan J, Flavell RA, Mullan M. T-cells in Alzheimer’s disease. Neuromolecular Med. 2005;7(3):255–64. https://doi.org/10.1385/NMM:7:3:255.CrossRefPubMed

24.

Willis SN, Tellier J, Liao Y, Trezise S, Light A, O’Donnell K, et al. Environmental sensing by mature B cells is controlled by the transcription factors PU.1 and SpiB. Nat Commun. 2017;8(1):1426. https://doi.org/10.1038/s41467-017-01605-1.CrossRefPubMedPubMedCentral

25.

van Olst L, Roks SJM, Kamermans A, Verhaar BJH, van der Geest AM, Muller M, et al. Contribution of gut microbiota to immunological changes in Alzheimer’s disease. Front Immunol. 2021;12: 683068. https://doi.org/10.3389/fimmu.2021.683068.PubMedPMID:34135909;PubMedCentralPMCID:PMCPMC8200826.CrossRefPubMedPubMedCentral

26.

You HY, Xie XM, Zhang WJ, Zhu HL, Jiang FZ. Berberine modulates cisplatin sensitivity of human gastric cancer cells by upregulation of miR-203. In Vitro Cell Dev Biol Anim. 2016;52(8):857–63. https://doi.org/10.1007/s11626-016-0044-y.CrossRefPubMed

27.

Zhao Y, Cong L, Jaber V, Lukiw WJ. microbiome-derived lipopolysaccharide enriched in the perinuclear region of Alzheimer’s disease brain. Front Immunol. 2017;8:1064. https://doi.org/10.3389/fimmu.2017.01064.CrossRefPubMedPubMedCentral

28.

Cattaneo A, Cattane N, Galluzzi S, Provasi S, Lopizzo N, Festari C, et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging. 2017;49:60–8. https://doi.org/10.1016/j.neurobiolaging.2016.08.019.CrossRefPubMed

29.

Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep. 2017;7(1):13537. https://doi.org/10.1038/s41598-017-13601-y.CrossRefPubMedPubMedCentral

30.

Zhuang ZQ, Shen LL, Li WW, Fu X, Zeng F, Gui L, et al. Gut Microbiota is Altered in Patients with Alzheimer’s Disease. J Alzheimers Dis. 2018;63(4):1337–46. https://doi.org/10.3233/JAD-180176.CrossRefPubMed

31.

Park JY, Choi J, Lee Y, Lee JE, Lee EH, Kwon HJ, et al. Metagenome analysis of bodily microbiota in a mouse model of Alzheimer disease using bacteria-derived membrane vesicles in blood. Exp Neurobiol. 2017;26(6):369–79. https://doi.org/10.5607/en.2017.26.6.369.CrossRefPubMedPubMedCentral

32.

Brandscheid C, Schuck F, Reinhardt S, Schafer KH, Pietrzik CU, Grimm M, et al. Altered gut microbiome composition and tryptic activity of the 5xFAD Alzheimer’s mouse model. J Alzheimers Dis. 2017;56(2):775–88. https://doi.org/10.3233/JAD-160926.CrossRefPubMed

33.

Shen L, Liu L, Ji HF. Alzheimer’s disease histological and behavioral manifestations in transgenic mice correlate with specific gut microbiome state. J Alzheimers Dis. 2017;56(1):385–90. https://doi.org/10.3233/JAD-160884.CrossRefPubMed

34.

Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep. 2017;7:41802. https://doi.org/10.1038/srep41802.CrossRefPubMedPubMedCentral

35.

Alam MT, Amos GCA, Murphy ARJ, Murch S, Wellington EMH, Arasaradnam RP. Microbial imbalance in inflammatory bowel disease patients at different taxonomic levels. Gut Pathog. 2020;12:1. https://doi.org/10.1186/s13099-019-0341-6.CrossRefPubMedPubMedCentral

36.

Lo DD. Vigilance or Subversion? Constitutive and Inducible M Cells in Mucosal Tissues. Trends Immunol. 2018;39(3):185–95. https://doi.org/10.1016/j.it.2017.09.002.CrossRefPubMed

37.

Kucharzik T, Lugering A, Lugering N, Rautenberg K, Linnepe M, Cichon C, et al. Characterization of M cell development during indomethacin-induced ileitis in rats. Aliment Pharmacol Ther. 2000;14(2):247–56. https://doi.org/10.1046/j.1365-2036.2000.00688.x.CrossRefPubMed

38.

Parnell EA, Walch EM, Lo DD. Inducible colonic M cells are dependent on TNFR2 but not ltbetar, identifying distinct signalling requirements for constitutive versus inducible M cells. J Crohns Colitis. 2017;11(6):751–60. https://doi.org/10.1093/ecco-jcc/jjw212.CrossRefPubMed

39.

Matsumura T, Sugawara Y, Yutani M, Amatsu S, Yagita H, Kohda T, et al. Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity. Nat Commun. 2015;6:6255. https://doi.org/10.1038/ncomms7255.CrossRefPubMed

40.

Lai NY, Musser MA, Pinho-Ribeiro FA, Baral P, Jacobson A, Ma P, et al. Gut-innervating nociceptor neurons regulate peyer’s patch microfold cells and SFB levels to mediate salmonella host defense. Cell. 2020;180(1):33-49.e22. https://doi.org/10.1016/j.cell.2019.11.014.CrossRefPubMed

41.

Malard F, Dore J, Gaugler B, Mohty M. Introduction to host microbiome symbiosis in health and disease. Mucosal Immunol. 2021;14(3):547–54. https://doi.org/10.1038/s41385-020-00365-4.CrossRefPubMed

42.

Szepesi Z, Manouchehrian O, Bachiller S, Deierborg T. Bidirectional microglia-neuron communication in health and disease. Front Cell Neurosci. 2018;12:323. https://doi.org/10.3389/fncel.2018.00323.CrossRefPubMedPubMedCentral

43.

Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol. 2010;177(5):2549–62. https://doi.org/10.2353/ajpath.2010.100265.CrossRefPubMedPubMedCentral

44.

Liu Z, Condello C, Schain A, Harb R, Grutzendler J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis. J Neurosci. 2010;30(50):17091–101. https://doi.org/10.1523/JNEUROSCI.4403-10.2010.CrossRefPubMedPubMedCentral

45.

Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18(7):965–77. https://doi.org/10.1038/nn.4030

46.

Kim MS, Kim Y, Choi H, Kim W, Park S, Lee D, et al. Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model. Gut. 2020;69(2):283–94. https://doi.org/10.1136/gutjnl-2018-317431.CrossRefPubMed

47.

Wang X, Sun G, Feng T, Zhang J, Huang X, Wang T, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res. 2019;29(10):787–803. https://doi.org/10.1038/s41422-019-0216-x.CrossRefPubMedPubMedCentral

48.

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 Immunol. 2013;190(5):2241–51. https://doi.org/10.4049/jimmunol.1200947.CrossRefPubMed

49.

Town T, Vendrame M, Patel A, Poetter D, DelleDonne A, Mori T, et al. Reduced Th1 and enhanced Th2 immunity after immunization with Alzheimer’s beta-amyloid(1–42). J Neuroimmunol. 2002;132(1–2):49–59. https://doi.org/10.1016/s0165-5728(02)00307-7.CrossRefPubMed

50.

Cao C, Arendash GW, Dickson A, Mamcarz MB, Lin X, Ethell DW. Abeta-specific Th2 cells provide cognitive and pathological benefits to Alzheimer’s mice without infiltrating the CNS. Neurobiol Dis. 2009;34(1):63–70. https://doi.org/10.1016/j.nbd.2008.12.015.CrossRefPubMedPubMedCentral

51.

McQuillan K, Lynch MA, Mills KH. Activation of mixed glia by Abeta-specific Th1 and Th17 cells and its regulation by Th2 cells. Brain Behav Immun. 2010;24(4):598–607. https://doi.org/10.1016/j.bbi.2010.01.003.CrossRefPubMed

Title: Inhibition of microfold cells ameliorates early pathological phenotypes by modulating microglial functions in Alzheimer’s disease mouse model
Authors: Namkwon Kim
In Gyoung Ju
Seung Ho Jeon
Yeongae Lee
Min-Ji Jung
Min Sung Gee
Jae Seok Cho
Kyung-Soo Inn
Lee Ann Garrett-Sinha
Myung Sook Oh
Jong Kil Lee
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Alzheimer's Disease
Alzheimer's Disease
Respiratory Microbiota
Published in: Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-023-02966-9

2024 ASCO Annual Meeting

Springer Medicine

Inhibition of microfold cells ameliorates early pathological phenotypes by modulating microglial functions in Alzheimer’s disease mouse model

Abstract

Background

Methods

Results

Conclusion

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2023

TREM2 deficiency inhibits microglial activation and aggravates demyelinating injury in neuromyelitis optica spectrum disorder

Progressive inflammation reduces high-frequency EEG activity and cortical dendritic arborisation in late gestation fetal sheep

Helicobacter pylori outer membrane vesicles induce astrocyte reactivity through nuclear factor-κappa B activation and cause neuronal damage in vivo in a murine model

Ogt-mediated O-GlcNAcylation inhibits astrocytes activation through modulating NF-κB signaling pathway

TSLP in DRG neurons causes the development of neuropathic pain through T cells

Unbiased multitissue transcriptomic analysis reveals complex neuroendocrine regulatory networks mediated by spinal cord injury-induced immunodeficiency