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

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., Rank 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.