Journal Article

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

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

2023

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Advertising executives / Alzheimer's disease / Antibodies / Antigens / B cells / Bacteria / Behavior / Biomedical and Life Sciences / Biomedicine / Brain / Care and treatment / Composition / Cytokines / Diagnosis / Disease / Ethylenediaminetetraacetic acid / Fecal microflora / Feces / Genetic aspects / Gut-brain axis / Immune response / Immunology / Inflammation / Intestinal microflora / Irritable bowel syndrome / Laboratory animals / M cells / Memory / Microbiota / Microbiota (Symbiotic organisms) / Microbiota-Gut-Brain axis / Microfold cells / Microglia / Neurobiology / Neurodegenerative diseases / Neurogenesis / Neurology / Neurosciences / Pathogenesis / Phenotypes / Proteins / The gut-brain axis: Emerging evidence in health and disease / β-Amyloid