miR155 triplicated in Down syndrome regulates hippocampal GABAergic neurogenesis in Alzheimer's disease

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Xiaodong Zhu, Jean-Vianney Haure-Mirande, Mesude Bicak

    Biorxiv : the Preprint Server for Biology
    |November 19, 2025
    PubMed

    Insights

    MicroRNA 155 (miR155) plays a dual role in Alzheimer's disease (AD) development. Neuronal miR155 influences neural stem cell proliferation and GABAergic interneuron generation, impacting AD neuropathology.

    Area of Science:

    • Neuroscience
    • Genetics
    • Molecular Biology

    Background:

    • MicroRNA dysregulation is linked to neurodegenerative diseases like Alzheimer's disease (AD).
    • Neuronal microRNA155 (miR155), elevated in AD and Down syndrome (DS), has an unknown function in neuronal development.
    • The MIR155HG gene, encoding miR155, is located on chromosome 21, which is triplicated in DS, leading to AD neuropathology.

    Purpose of the Study:

    • To investigate the role of neuronal miR155 in neural stem cell (NSC) development and GABAergic interneuron generation.
    • To validate these findings in an amyloidopathy mouse model.
    • To understand the distinct roles of miR155 in neurons versus microglia for potential therapeutic strategies in AD.

    Main Methods:

    • Utilized human induced pluripotent stem cell (hiPSC)-derived NSCs, cortical neurons, and organoids.
    • Investigated the effects of MIR155 deletion and overexpression on NSC proliferation, differentiation, and gene expression.
    • Employed an amyloidopathy mouse model to assess miR155's impact in vivo.
    • Analyzed miR155's regulation of NR2F1/2 mRNA targets.

    Main Results:

    • MIR155 deletion in human cells enhanced NSC proliferation and GABAergic interneuron generation.
    • MIR155 overexpression inhibited NSC marker expression and GABAergic interneuron development.
    • miR155 deletion in a mouse model increased hippocampal NSCs and GABAergic interneurons.
    • miR155 was found to upregulate NR2F1/2, key regulators of hippocampal interneuron development.

    Conclusions:

    • Neuronal miR155 plays a significant role in regulating NSC dynamics and GABAergic interneuron development.
    • The function of miR155 in neurons diverges from its role in microglia, with opposing effects in AD models.
    • Therapeutic targeting of miR155 in AD may require a nuanced approach to balance its effects in different cell types.

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