First and second generation γ-secretase modulators (GSMs) modulate amyloid-β (Aβ) peptide production through different mechanisms.

Borgegard T, Juréus A, Olsson F, Rosqvist S, Sabirsh A, Rotticci D, Paulsen K, Klintenberg R, Yan H, Waldman M, Stromberg K, Nord J, Johansson J, Regner A, Parpal S, Malinowsky D, Radesater AC, Li T, Singh R, Eriksson H, Lundkvist J.
Journal   J Biol Chem.
Species  
Analytes Measured   Abeta 38 , Abeta 40 , Abeta 42
Matrix Tested   Cell culture supernatants, cell membrane suspensions
Year   2012
Volume   287
Page Numbers   11810-11819
Application   Alzheimers
Abstract
γ-Secretase-mediated cleavage of amyloid precursor protein (APP) results in the production of Alzheimer disease-related amyloid-β (Aβ) peptides. The Aβ42 peptide in particular plays a pivotal role in Alzheimer disease pathogenesis and represents a major drug target. Several γ-secretase modulators (GSMs), such as the nonsteroidal anti-inflammatory drugs (R)-flurbiprofen and sulindac sulfide, have been suggested to modulate the Alzheimer-related Aβ production by targeting the APP. Here, we describe novel GSMs that are selective for Aβ modulation and do not impair processing of Notch, EphB2, or EphA4. The GSMs modulate Aβ both in cell and cell-free systems as well as lower amyloidogenic Aβ42 levels in the mouse brain. Both radioligand binding and cellular cross-competition experiments reveal a competitive relationship between the AstraZeneca (AZ) GSMs and the established second generation GSM, E2012, but a noncompetitive interaction between AZ GSMs and the first generation GSMs (R)-flurbiprofen and sulindac sulfide. The binding of a (3)H-labeled AZ GSM analog does not co-localize with APP but overlaps anatomically with a γ-secretase targeting inhibitor in rodent brains. Combined, these data provide compelling evidence of a growing class of in vivo active GSMs, which are selective for Aβ modulation and have a different mechanism of action compared with the original class of GSMs described.

View Publications

Related Products

R-PLEX Human Aβ42 (6E10) Antibody Set
Aβ42 (6E10) | Human
Singleplex
NEW
R-PLEX Human Aβ40 (6E10) Antibody Set
Aβ40 (6E10) | Human
Singleplex
NEW
Human (6E10) Aβ38 Ultra-Sensitive Kit
Aβ38 | Human
Singleplex
Human (6E10) Aβ40 Ultra-Sensitive Kit
Aβ40 | Human
Singleplex
Human (6E10) Aβ42 Ultra-Sensitive Kit
Aβ42 | Human
Singleplex
V-PLEX Human Aβ42 Kit
Aβ42 | Human
Singleplex
V-PLEX Aβ Peptide Panel 1 (4G8) Kit
Aβ38, Aβ40, Aβ42 | Human, Mouse, Rat
Multiplex
V-PLEX Aβ Peptide Panel 1 (6E10) Kit
Aβ38, Aβ40, Aβ42 | Human
Multiplex
V-PLEX Aβ40 Peptide (4G8) Kit
Aβ40 | Human, Mouse, Rat
Singleplex
V-PLEX Aβ40 Peptide (6E10) Kit
Aβ40 | Human
Singleplex
V-PLEX Aβ42 Peptide (4G8) Kit
Aβ42 | Human, Mouse, Rat
Singleplex
V-PLEX Plus Aβ Peptide Panel 1 (4G8) Kit
Aβ38, Aβ40, Aβ42 | Human, Mouse, Rat
Multiplex
V-PLEX Plus Aβ Peptide Panel 1 (6E10) Kit
Aβ38, Aβ40, Aβ42 | Human
Multiplex
V-PLEX Plus Aβ40 Peptide (4G8) Kit
Aβ40 | Human, Mouse, Rat
Singleplex
V-PLEX Plus Aβ40 Peptide (6E10) Kit
Aβ40 | Human
Singleplex
V-PLEX Plus Aβ42 Peptide (4G8) Kit
Aβ42 | Human, Mouse, Rat
Singleplex
V-PLEX Plus Human Aβ42 Kit
Aβ42 | Human
Singleplex
Neurodegeneration Control Pack 1
Aβ38, Aβ40, Aβ42, Tau (total) | Human, Mouse, Rat
V-PLEX Aβ38 Peptide (4G8) Kit
Aβ38 | Human, Mouse, Rat
Singleplex
V-PLEX Aβ38 Peptide (6E10) Kit
Aβ38 | Human
Singleplex
V-PLEX Plus Aβ38 Peptide (4G8) Kit
Aβ38 | Human, Mouse, Rat
Singleplex
V-PLEX Plus Aβ38 Peptide (6E10) Kit
Aβ38 | Human
Singleplex
Browse Our Products

By Analytes
By Applications
Search
Customer Service/Orders


Scientific/Technical Support


Instrument Support


Company Headquarters