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Gut miRNA regulates gut microbiome and Alzheimer pathology in App-knock-in mice

Hao, W.; Luo, Q.; Szabo, I. M.; Gasparoni, G.; Tierling, S.; Quan, W.; Chang, H.-F.; Wu, G.; Schulze-hentrich, J.; Liu, Y.

2025-06-08 neuroscience
10.1101/2025.06.05.658056 bioRxiv
Show abstract

Alzheimers disease (AD) alters the gut microbiome. It remains unclear whether manipulation of miRNA could modulate the gut microbiome and AD pathologies. Depletion of gut miRNA in App-knock-in mice by conditional knockout of Dicer1 gene in intestinal epithelial cells: 1) decreased the absolute number and changed the composition of bacteria in both the gut and brain; 2) reduced cerebral A{beta} load by inhibiting {beta}-secretase activity and increasing the expression of LRP1 and ABCB1 at the blood-brain barrier; 3) increased Il-10 transcription and decreased the transcription of Ccl-2 gene, and that of Ndufa2 and Ndufa5 genes encoding mitochondrial respiratory enzymes in the brain; and 4) induced anxiety symptoms without affecting cognitive function in AD mice. Thus, manipulating miRNA in the gut can modify AD pathogenesis. Future studies should focus on identifying AD-specific miRNAs in the gut that can be therapeutically exploited (e.g. by oral administration) to prevent the progression of AD.

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