Catalytic site-directed γ-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and β-APP cleavages

Abstract:

The generation of γ-secretase inhibitors which block the release of β-amyloid peptide (Aβ) has long been an attractive therapeutic avenue for treatment or prevention of Alzheimer's disease (AD). Such inhibitors would reduce levels of Aβ available for aggregation into toxic assemblies that lead to the plaque pathology found in affected brain tissue. Cumulative evidence suggests that the S3 cleavage of Notch is also dependent on presenilins (PS) and is carried out by the multimeric PS-containing γ-secretase complex. It is therefore possible that Notch function could be affected by γ-secretase inhibitors. To assess the relationship between the cleavage of these substrates in the same system, Western blot cleavage assays have been established using a human cell line stably expressing both the β-amyloid precursor protein (β-APP) and the truncated Notch1 receptor fragment NotchΔE. Thus, a direct correlation may be …

Año de publicación:

2003

Keywords:

Fuente:

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