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bioRxiv · 10.1101/2025.06.05.658056

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.
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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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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. Gut miRNA regulates gut microbiome and Alzheimer pathology in App-knock-in mice. https://doi.org/10.1101/2025.06.05.658056

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