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Effects of Intestinal M Cells on Intestinal Barrier and Neuropathological Properties in an AD Mouse Model

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Abstract

Intestinal microfold cells (M cells) play a critical role in the immune response of the intestinal mucosa by actively taking up antigens, facilitating antigen presentation to immune cells, and promoting the production of secretory immunoglobulin A by B cells. Despite their known important functions in the gut, the effect of M cells on the central nervous system remains unclear. We investigated the expression of M cell-related factor genes and protein levels in Peyer’s patches (PPs) of 3-month-old and 9-month-old APP/PS1 mice, as well as the expression of intestinal barrier proteins in the ileum and colon of these mice. Furthermore, we employed intestinal M cell conditional ablation mice (i.e., RankΔIEC mice) to assess the influence of M cells on the intestinal barrier and Alzheimer’s disease (AD)-like behavioral and pathological features. Our findings revealed that compared to wild-type mice, APP/PS1 mice showed altered M cell-related genes and disrupted intestinal barriers. In addition, there is a significant decrease in glycoprotein 2 (GP2) mRNA levels in the PPs of 3-month-old APP/PS1 mice, with the relative expression of GP2 mRNA tending to zero. Parameters related to the intestinal barrier (IgA, MUC2, Claudin-5, ZO-1) were significantly downregulated in both 3-month-old and 9-month-old APP/PS1 mice compared to wild-type controls, and the differences were more pronounced in the 9-month-old mice. Moreover, M cell ablation in APP/PS1 mice (i.e., APP/PS1ΔMC mice) resulted in more severe intestinal barrier destruction. Notably, we observed through water maze experiments that APP/PS1ΔMC mice at 6 months of age exhibited significantly poorer spatial learning memory compared to APP/PS1 mice. And the neuropathological alterations were also observed in APP/PS1ΔMC mice at 6 months of age that when intestinal M cells are damaged in APP/PS1 mice, brain microglia are activated, Tau phosphorylation is exacerbated, and the number of neurons is reduced. Our results suggest for the first time that the absence of intestinal M cells might further aggravate intestinal leakage, lead to neuropathological damage, and subsequently cause the impairment of learning memory ability in AD mice. Our research highlights the impact of intestinal M cells on the intestinal barrier and AD neuropathogenesis in AD mouse model.

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Data Availability

All data generated or analyzed during this study are included in this published article. And the datasets used and/or analyzed in the current study are available from the corresponding authors on reasonable request.

Abbreviations

M cell:

Microfold cell

SIgA:

Secretory immunoglobulin A

AD:

Alzheimer’s disease

Aβ:

Amyloid beta

FAE:

Follicle-associated epithelium

PPs:

Peyer’s patches

GP2:

Glycoprotein 2

Ig:

Immunoglobulin

PBS:

Phosphate-buffered saline

MUC2:

Mucin-2

ZO-1:

Zonula occludens-1

MAP 2:

Microtubule-associated protein 2

AT8:

p-Tau(Ser202, Thr205)

pT231:

Phospho-Tau (Thr231)

pS396:

Phospho-Tau (Ser396)

GSK-3β:

Glycogen synthase kinase 3 beta

qRT-PCR:

Quantitative real-time polymerase chain reaction

WT:

Wild type

Rank:

Receptor activator of nuclear factor κB

Tnfaip2:

Tumor necrosis factor alpha-induced protein 2

LPS:

Lipopolysaccharide

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Acknowledgements

We appreciate the help from Gempharmatech Co., Ltd. and Shanghai Model Organisms Center, Inc.

Funding

This work was supported by Clinic and Basic Research Project of Guangdong Medical University (grant number 4SG23284G), the Science and Technology Planning Project of Zhanjiang (grant number 2021A05071 and 2020B01395), and of GDMU (grant number GDMUQ2021047 and GDMU2021122).

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  1. Shijing Wu, Li Hu and Yiwei Fu contributed equally to this work.

Authors and Affiliations

  1. Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China

    Shijing Wu, Li Hu, Yiwei Fu, Yating Chen, Zhibin Hu & Zhou Liu

  2. Department of Histology and Embryology, Guangdong Medical University, Zhanjiang, Guangdong, China

    Li Hu

  3. Wolfson Institute for Biomedical Research, University College London, London, WC1E 6BT, UK

    Huiliang Li

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Contributions

ZL conceived the conception and contributed to literature search and drafting. SJW, LH, and ZBH performed the experiments and analyzed the data. SJW, YWF, and YTC prepared the manuscript with contributions from all authors. ZL and HLL supervised the project and contributed to the revision of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Huiliang Li or Zhou Liu.

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All the animal experimental procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals and approved by the laboratory animal ethical committee of Guangdong Medical University.

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Wu, S., Hu, L., Fu, Y. et al. Effects of Intestinal M Cells on Intestinal Barrier and Neuropathological Properties in an AD Mouse Model. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03807-9

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