Related Experiment Video

Updated: Sep 9, 2025

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission

Published on: August 16, 2018

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As48, a First-in-Class Dual-Function TREM2 Modulator: Receptor Activation and Shedding Inhibition

Sungwoo Cho, Farida El Gaamouch, Saurabh Upadhyay

    Biorxiv : the Preprint Server for Biology
    |September 5, 2025
    PubMed

    Insights

    A new drug, As48, activates TREM2 signaling and prevents its shedding, offering a novel therapeutic strategy for Alzheimer's disease by enhancing microglial function and brain repair mechanisms.

    Area of Science:

    • Neuroscience
    • Immunology
    • Pharmacology

    Background:

    • Triggering receptor expressed on myeloid cells 2 (TREM2) dysfunction is implicated in Alzheimer's disease (AD) pathogenesis.
    • ADAM-mediated TREM2 shedding reduces receptor signaling efficacy, a challenge for current therapeutics.

    Purpose of the Study:

    • To identify novel small molecules that modulate TREM2 activity.
    • To develop therapeutics that enhance TREM2 signaling and prevent receptor shedding for Alzheimer's disease treatment.

    Main Methods:

    • Affinity Selection-Mass Spectrometry (AS-MS) screening to identify TREM2 ligands.
    • Biophysical validation, cellular assays (SYK phosphorylation, phagocytosis), molecular docking, and molecular dynamics simulations.
    • Assessment of As48's effect on TREM2 ectodomain shedding and protease activity (ADAM10/17).

    Main Results:

    • As48, a novel small molecule, binds TREM2 with high affinity and selectivity over TREM1.
    • As48 acts as a TREM2 agonist, enhancing microglial phagocytosis and SYK phosphorylation.
    • As48 inhibits TREM2 shedding by conformational restriction near the cleavage site, without affecting protease activity.
    • As48 demonstrates favorable pharmacokinetics and potential for brain permeability.

    Conclusions:

    • As48 is the first small molecule shown to both activate TREM2 signaling and inhibit its shedding.
    • As48 represents a paradigm shift in TREM2 modulation for neuroinflammation and Alzheimer's disease drug discovery.
    • The dual-action mechanism of As48 offers significant translational relevance for treating neurodegenerative diseases.

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