Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Concept Videos

Nondepolarizing (Competitive) Neuromuscular Blockers: Mechanism of Action01:17

Nondepolarizing (Competitive) Neuromuscular Blockers: Mechanism of Action

Nondepolarizing neuromuscular blockers induce paralysis by competitively blocking nicotinic acetylcholine receptors at the muscle end plate. Examples include pancuronium, mivacurium, vecuronium, and rocuronium. These quaternary ammonium derivatives are administered intravenously, are poorly absorbed, and are excreted via the kidneys.
Competitive antagonists prevent acetylcholine from binding to its receptor, inhibiting membrane depolarization. Without conformational changes or intrinsic...
Ligand-Gated Ion Channel Receptor: Gating Mechanism01:30

Ligand-Gated Ion Channel Receptor: Gating Mechanism

Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
Alzheimer's Disease: Treatment01:22

Alzheimer's Disease: Treatment

Alzheimer's Disease (AD), a neurodegenerative disorder, is pathologically identified by amyloid plaques and neurofibrillary tangles composed of tau protein. AD pharmacotherapy aims to manage cognitive symptoms, delay disease progression, and treat behavioral symptoms. The treatment is primarily symptomatic and palliative, with no definitive disease-modifying therapy available. Cholinesterase inhibitors, including donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne), are...
Amyloid Fibrils03:03

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
Amyloid deposits were observed as early as 1639 in the liver and the spleen.   In 1854, Rudolph Virchow performed iodine staining, normally used to...
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:29

Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship

Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Indirect-Acting Cholinergic Agonists: Mechanism of Action01:18

Indirect-Acting Cholinergic Agonists: Mechanism of Action

Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Protein-enhanced small molecule disruptors of ordered membrane domains.

Proceedings of the National Academy of Sciences of the United States of America·2026
Same author

Stable and Tunable Expression of Human Peripheral Myelin Protein 22 in Rat Schwann Cells.

The Journal of biological chemistry·2026
Same author

Peripheral Myelin Protein-22 and Its Prominence in Charcot-Marie-Tooth Disease.

Chemical reviews·2026
Same author

High-throughput screening identifies a trafficking corrector for long QT syndrome-associated KCNQ1 variants.

JCI insight·2026
Same author

Pharmacological tools to modulate ordered membrane domains and order-dependent protein function.

Communications chemistry·2026
Same author

Classification models distinguish functional and trafficking effects of KCNQ1 variants to enhance variant interpretation.

bioRxiv : the preprint server for biology·2025

Related Experiment Video

Updated: May 28, 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

NSAID-based γ-secretase modulators do not bind to the amyloid-β polypeptide.

Paul J Barrett1, Charles R Sanders, Stephen A Kaufman

  • 1Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232-8725, United States.

Biochemistry
|October 15, 2011
PubMed
Summary

Gamma-secretase modulators (GSMs) for Alzheimer's disease may not work by directly binding amyloid-beta. Instead, some GSMs aggregate and nonspecifically trigger amyloid-beta aggregation, challenging current therapeutic hypotheses.

More Related Videos

Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by γ-Secretase
11:57

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

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP
07:55

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP

Published on: October 17, 2015

Related Experiment Videos

Last Updated: May 28, 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

Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by γ-Secretase
11:57

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

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP
07:55

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP

Published on: October 17, 2015

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Alzheimer's disease (AD) therapeutics target amyloid-beta (Aβ) production via gamma-secretase modulators (GSMs).
  • GSMs are hypothesized to work by directly binding to the Aβ domain of the C-terminal fragment of amyloid precursor protein (C99).
  • The precise mechanism of action for GSMs remains poorly understood, necessitating further investigation into their molecular interactions.

Purpose of the Study:

  • To investigate the interaction between the GSM sulindac sulfide and amyloid-beta (Aβ) species.
  • To determine if NSAID-based GSMs directly bind to Aβ or C99, challenging existing hypotheses.
  • To explore the aggregation behavior of GSMs and its potential impact on experimental results.

Main Methods:

  • Investigated the binding of monomeric sulindac sulfide to monomeric Aβ42.
  • Observed the aggregation properties of sulindac sulfide in solution.
  • Examined the binding of flurbiprofen to monomeric Aβ42 and C99 reconstituted into lipid vesicles.

Main Results:

  • No direct interaction was found between monomeric sulindac sulfide and monomeric Aβ42.
  • Sulindac sulfide was observed to form aggregates that could nonspecifically bind to and induce Aβ42 aggregation.
  • Flurbiprofen also failed to bind to monomeric Aβ42 or C99, further questioning direct binding mechanisms.

Conclusions:

  • The aggregation of sulindac sulfide can confound binding assay results, suggesting current interpretations may be flawed.
  • NSAID-based GSMs likely do not function by directly targeting the Aβ domain of C99.
  • These findings challenge the direct binding hypothesis for NSAID-based GSMs and suggest alternative mechanisms of action for Alzheimer's disease therapeutics.