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bioRxiv · 10.1101/2023.12.06.570400

Modulation of Alzheimer's Disease Brain Pathology in Mice by Gut Bacterial Deletion: The Role of Il-17a and Microglial MyD88

Hao, W.·Luo, Q.·Tomic, I.·Quan, W.·Hartmann, T.·Menger, M.·Fassbender, K.·Liu, Y.
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Abstract

Gut bacteria regulate brain pathology of Alzheimers disease (AD) patients and animal models; however, the underlying mechanism remains unclear. In this study, 3-month-old APP-transgenic female mice with and without knock-out of Il-17a gene, or haploinsufficiency of MyD88 in microglia were treated with antibiotics-supplemented or normal drinking water for 2 months. Antibiotic treatment eradicated gut bacteria, particularly in the phyla Bacteroidetes and Firmicutes, and reduced Il-17a-expressing CD4-positive T lymphocytes. Deletion of gut bacteria inhibited inflammatory activation in the brain and microglia, and reduced cerebral A{beta} levels in APP-transgenic mice, which was abolished by deficiency of Il-17a or haploinsufficiency of MyD88 in microglia. As possible mechanisms regulating A{beta} pathology, deletion of gut bacteria inhibited {beta}-secretase activity and increased the expression of Abcb1 and Lrp1 in the brain or at the blood-brain barrier, which were also reversed by the absence of Il-17a. Interestingly, a crossbreeding experiment between APP-transgenic mice and Il-17a knockout mice further showed that deficiency of Il-17a had already increased Abcb1 and Lrp1 expression at the blood-brain barrier. Thus, deletion of gut bacteria attenuates inflammatory activation and amyloid pathology in APP-transgenic mice via Il-17a and microglial MyD88-involved signalling pathways. Our study contributes to a better understanding of the gut-brain axis in AD pathophysiology.

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Hao, W., Luo, Q., Tomic, I., Quan, W., Hartmann, T., Menger, M., Fassbender, K., Liu, Y.. 2023-12-06. Modulation of Alzheimer's Disease Brain Pathology in Mice by Gut Bacterial Deletion: The Role of Il-17a and Microglial MyD88. https://doi.org/10.1101/2023.12.06.570400

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