Catalytic Site-Directed γ-Secretase Complex Inhibitors Do Not Discriminate Pharmacologically between Notch S3 and β-APP Cleavages
Huw D. LewisBlanca I. Pérez RevueltaAlan NadinJoe G. NeduvelilTimothy HarrisonScott J. PollackMark S. Shearman
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Abstract:
The generation of gamma-secretase inhibitors which block the release of beta-amyloid peptide (Abeta) has long been an attractive therapeutic avenue for treatment or prevention of Alzheimer's disease (AD). Such inhibitors would reduce levels of Abeta 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 gamma-secretase complex. It is therefore possible that Notch function could be affected by gamma-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 beta-amyloid precursor protein (beta-APP) and the truncated Notch1 receptor fragment NotchDeltaE. Thus, a direct correlation may be made, following inhibitor treatment, of the decrease in the levels of the cleavage products, Abeta peptide and the Notch intracellular domain (NICD), as well as the increase in stabilized levels of both substrates. This analysis has been performed with a range of selected gamma-secretase inhibitors from six distinct structural classes. Changes in all four species usually occur in concert and with remarkably good agreement. A significant cleavage window is not clearly apparent in any case. Thus, these Notch and beta-APP cleavages cannot be dissected apart easily since they show the same pharmacological profile of inhibition. Whether this translates into proportionally reduced Notch signaling in vivo, however, remains to be seen.Keywords:
Gamma secretase
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Gamma-secretase catalyzes proteolysis within cell membranes as the last step in the formation of amyloid-beta from its precursor protein (APP). This protease is comprised of four different membrane proteins, with presenilin as the catalytic component. Small molecule probes have been essential for characterizing and identifying this enzyme as well as advancing the understanding of its catalytic mechanism. Gamma-secretase also cleaves other membrane proteins besides APP, the most notorious being the Notch receptor. Because Notch signaling is critical for cell differentiation, gamma-secretase inhibitors that block both APP and Notch proteolysis can cause severe toxicities by interfering with essential processes such as hematopoiesis. However, the recent identification of compounds that modulate the gamma-secretase complex to reduce amyloid-beta without affecting Notch signaling have renewed hope in this protease as a therapeutic target.
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Hes3 signaling axis
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Alzheimer's disease (AD) research has shown that patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-β (the primary component of the amyloid deposits found in AD brains). However, it is not clear how the presenilins contribute to this increase. New findings now show that the presenilins affect APP processing through their effects on γ-secretase, an enzyme that cleaves APP. Also, it is known that the presenilins are involved in the cleavage of the Notch receptor, hinting that they either directly regulate γ-secretase activity or themselves are protease enzymes. These findings suggest that the presenilins may prove to be valuable molecular targets for the development of drugs to combat AD.
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gamma-Secretase is a four subunit, 19-pass transmembrane enzyme that cleaves amyloid precursor protein, catalyzing the formation of amyloid beta peptides that form amyloid plaques, which contribute to Alzheimer's disease pathogenesis. gamma-Secretase also cleaves Notch, among many other type I transmembrane substrates. Despite its seemingly promiscuous enzymatic capacity, gamma-secretase activity is tightly regulated. This regulation is a function of many cellular entities, including but not limited to the essential gamma-secretase subunits, nonessential (modulatory) subunits, and gamma-secretase substrates. Regulation is also accomplished by an array of cellular events, such as presenilin (active subunit of gamma-secretase) endoproteolysis and hypoxia. In this review we discuss how gamma-secretase is regulated with the hope that an advanced understanding of these mechanisms will aid in the development of effective therapeutics for gamma-secretase-associated diseases like Alzheimer's disease and Notch-addicted cancer
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