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Product Feature - γ-Secretase Inhibitors
γ-secretase is a multi-subunit internal protease that cleaves single pass transmembrane proteins within the transmembrane domain. It is itself an integral membrane protein and minimally consists of 4 proteins: presenilin, nicastrin, APH-1 and PEN-2. Presenilin is an aspartic protease and the catalytic subunit of the complex.
Key γ-secretase inhibitors now available from Tocris include:
Inhibitor of γ-secretase
2634 l DAPT Causes a reduction in Aβ40 and Aβ42 levels in human primary neuronal cultures (IC50 values are 115 and 200 nM for total Aβ and Aβ42 respectively) and in brain extract, cerebrospinal fluid and plasma in vivo.
Inhibitor of γ-secretase-mediated βAPP processing
2677 l JLK 6 Selectively inhibits βAPP cleavage without affecting other γ-secretase-mediated pathways.
Inhibitor of γ-secretase
2654 l Compound W Causes a decrease in the released levels of Aβ42 and notch-1 Aβ-like peptide 25 (Nβ25).
View all γ-secretase Related Products.
γ-secretase and Alzheimer's disease
The best known substrate of γ-secretase is the transmembrane amyloid precursor protein (APP). APP is cleaved first by β-secretase and then by γ-secretase to produce amyloid beta (Aβ) peptides of 39-42 amino acids in length. The abnormally folded fibrillary form of Aβ (predominantly Aβ42) is the primary component of amyloid plaques found in the brains of Alzheimer’s disease patients. Mutations in both APP and presenilin are associated with early onset Alzheimer’s as a result of increased production of Aβ42.
γ-secretase and Notch
The Notch receptor is a single membrane spanning protein involved in cell differentiation. Upon ligand binding, the extracellular domain is cleaved by a metalloprotease named TACE. γ-secretase cleaves within the transmembrane domain of the remaining Notch protein releasing the intracellular domain (Nβ) into the cytoplasm. Nβ moves to the nucleus where it can regulate gene expression by activating the transcription factor CSL.
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