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bioRxiv · 10.64898/2026.06.11.731747

MicroRNA-181 influences Alzheimer's risk by regulating neprilysin and microtubule-associated tau pathways, offering a novel target

Wang, R.·Maloney, B. J.·Nho, K.·Beck, J. S.·Counts, S. E.·Lahiri, D. K.
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Abstract

Alzheimers disease (AD) is characterized by amyloid-{beta} (A{beta}) peptide plaques and neurofibrillary tangles from hyperphosphorylated tau, though factors linking amyloid and tau pathology remain unclear. We investigated whether microRNA-181d-5p (miR-181d) associates with AD-related brain changes and regulates neprilysin and tau. Modeling miR-181d across individuals with no cognitive impairment, mild cognitive impairment, and AD revealed region- and sex-specific associations. Higher miR-181d levels associated with greater AD probability in the temporal lobe and cerebellum, and lower probability in the posterior cingulate cortex of males; miR-181c attenuated these probabilities. SNPs near MIR181 associated with altered entorhinal cortical thickness. In cellular models, miR-181 reduced neprilysin 3'-UTR activity, mRNA, protein, and enzymatic activity, while increasing tau mRNA and protein. Neprilysin diminution impairs A{beta} clearance and elevates tau, contributing to AD. RNA sequencing identified miR-181d-responsive neurodegenerative pathways. These findings identify miR-181 as a regulator of AD-relevant amyloid and tau pathways, providing novel targets. TeaserMiRNA-181 is a key regulator of Alzheimers risk through its effects on neprilysin and tau proteins, a novel potential target.

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Wang, R., Maloney, B. J., Nho, K., Beck, J. S., Counts, S. E., Lahiri, D. K.. 2026-06-16. MicroRNA-181 influences Alzheimer's risk by regulating neprilysin and microtubule-associated tau pathways, offering a novel target. https://doi.org/10.64898/2026.06.11.731747

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