Related Experiment Video

Updated: Jan 9, 2026

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
07:16

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

Published on: August 16, 2018

14.2K

As48, a first-in-class dual-function TREM2 modulator: Receptor activation and shedding inhibition

Sungwoo Cho1, Farida El Gaamouch1, Saurabh Upadhyay1

  • 1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, NY 10065, USA.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|December 3, 2025
PubMed

Insights

A novel small molecule, As48, activates TREM2 signaling and enhances microglial phagocytosis. It also prevents TREM2 receptor shedding, offering a new therapeutic strategy for Alzheimer's disease neuroinflammation.

Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Triggering receptor expressed on myeloid cells 2 (TREM2) dysfunction is implicated in Alzheimer's disease (AD) pathogenesis.
  • Current AD therapeutics do not address ADAM-mediated TREM2 receptor shedding, which reduces signaling efficacy.

Purpose of the Study:

  • To identify novel small molecules that modulate TREM2 activity.
  • To investigate the potential of As48 as a therapeutic agent for AD by examining its effects on TREM2 activation and shedding.

Main Methods:

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

Main Results:

  • As48 identified as a high-affinity TREM2 binder with high selectivity over TREM1.
  • As48 demonstrated TREM2 agonism, enhancing microglial phagocytosis and SYK phosphorylation.
  • As48 inhibited TREM2 shedding by conformationally restricting protease accessibility, without affecting ADAM10/17 activity.
  • As48 exhibited favorable pharmacokinetics with potential for brain permeability.

Conclusions:

  • As48 is the first small molecule shown to inhibit TREM2 shedding via conformational restriction.
  • As48's dual action of promoting TREM2 activation and preventing shedding presents a novel therapeutic approach for neuroinflammation in AD.
  • As48 shows translational relevance for Alzheimer's disease drug discovery.
Keywords:
ADAM shedding inhibitionAlzheimer's diseaseDual functionalityMicrogliaTREM2

More Related Videos

Author Spotlight: Developing Parmodulins to Target Protease-Activated Receptors for Inflammation Control07:13

Author Spotlight: Developing Parmodulins to Target Protease-Activated Receptors for Inflammation Control

Published on: May 24, 2024

907
Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay09:03

Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay

Published on: March 10, 2020

13.6K

Related Concept Videos

GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
7.9K
Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...
3.9K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
2.7K
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
17.8K
The Two-State Receptor Model01:29

The Two-State Receptor Model

The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with...
3.0K
Drug-Receptor Interaction: Agonist01:25

Drug-Receptor Interaction: Agonist

Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous...
3.7K