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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...
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Targets for Drug Action: Overview

Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
Antiepileptic Drugs: GABAergic Pathway Potentiators01:18

Antiepileptic Drugs: GABAergic Pathway Potentiators

γ-aminobutyric acid or GABA, plays a pivotal role as an inhibitory neurotransmitter in the brain. GABA pathway potentiators, also known as GABAergic drugs, are a class of pharmaceutical agents designed to enhance the functioning of the GABAergic system. These medications primarily treat epilepsy, a neurological disorder characterized by recurrent seizures.
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Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein01:20

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Modified-Release Drug Delivery Systems: Site-Targeted01:24

Modified-Release Drug Delivery Systems: Site-Targeted

Site-targeted drug delivery systems enhance therapeutic efficacy while minimizing systemic toxicity and treatment costs. Unlike conventional methods, these systems ensure precise drug delivery, improving bioavailability and reducing side effects. Targeted drug delivery is classified into three levels. First-order targeting directs drugs to the capillary beds of specific organs or tissues. Second-order targets specific cell types, such as tumor cells, using receptor-mediated interactions.
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Related Experiment Video

Updated: May 11, 2026

Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
06:40

Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms

Published on: January 25, 2018

Substrate-targeting gamma-secretase modulators.

Thomas L Kukar1, Thomas B Ladd, Maralyssa A Bann

  • 1Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA. kukar.thomas@mayo.edu

Nature
|June 13, 2008
PubMed
Summary
This summary is machine-generated.

Small-molecule gamma-secretase modulators (GSMs) target amyloid precursor protein (APP) and amyloid-beta, not the gamma-secretase complex itself. This dual action may offer a synergistic approach for Alzheimer's disease therapy.

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Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by γ-Secretase
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Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by γ-Secretase

Published on: June 24, 2025

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Alzheimer's disease (AD) therapy targets lowering amyloid-beta 42 (Abeta42) using gamma-secretase modulators (GSMs).
  • The precise molecular target of GSMs within the gamma-secretase pathway remains incompletely understood.
  • Identifying GSM targets is crucial for developing effective AD therapeutics.

Purpose of the Study:

  • To identify the direct molecular targets of small-molecule gamma-secretase modulators (GSMs).
  • To elucidate the mechanism by which GSMs modulate Abeta42 production and amyloid-beta aggregation.
  • To explore the therapeutic potential of substrate-targeting GSMs for Alzheimer's disease.

Main Methods:

  • Development and application of biotinylated photoactivatable GSMs (photoprobes).
  • Affinity labeling assays in human neuroglioma H4 cells to identify protein targets.
  • Competition assays with various GSMs and substrate-specific labeling experiments.
  • Site-directed mutagenesis of the amyloid precursor protein (APP) binding site.

Main Results:

  • GSM photoprobes labeled the amyloid precursor protein (APP), its carboxy-terminal fragments, and amyloid-beta peptide, but not core gamma-secretase components.
  • GSM interaction was localized to residues 28-36 of amyloid-beta, a region critical for aggregation.
  • GSMs altered the production of cell-derived amyloid-beta oligomers, and APP mutations affected GSM sensitivity.
  • Substrate labeling by GSMs was more efficient for APP than for Notch.

Conclusions:

  • GSMs act by directly targeting the APP substrate, not the gamma-secretase enzyme complex.
  • This substrate-targeting mechanism links modulation of Abeta42 production with inhibition of amyloid-beta aggregation.
  • This dual action offers a potentially synergistic therapeutic strategy for Alzheimer's disease, broadening the concept of druggable targets.