β-and γ-Secretase Inhibitors

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Introduction

The Aβ region of APP contains a sequence of 42-43 amino acid residues, partially located in the extracellular domain and partially in the transmembrane domain of APP. APP is cleaved by three types of proteases, called α-,β-and γ-secretase. Proteolytic cleavage of amyloid from amyloid precursor (APP) by APP secretase is a key event in the pathogenesis of Alzheimer’s disease (AD). The α-secretase cleaves APP within the amyloid sequence, while the β- and γ-secretase cleave at the N- and C-termini, respectively. The transmembrane aspartyl protease BACE has been identified as a beta-secretase, and several proteases (ADAM-10, TACE, PC7) may be α-secretase. β-secretase and γ-secretase are involved in the production of β-amyloid components in senile plaques in the brains of patients with Alzheimer's disease, and have driven the main research work to design these selective protease inhibitors. Interestingly, γ-secretase cleaves several proteins, including Notch, E-cadherin, CD44 and ErbB-4 (erythroblast leukemia virus oncogene homolog 4), which are important regulators of angiogenesis. The β-amyloid precursor protein, which is cleaved by β-secretase and γ-secretase to produce β-amyloid, is highly expressed in the endothelium of neovascularization, suggesting that it may play a role in angiogenesis.

Mechanism of action

The researchers further explored the effects of different structures of beta and γ-secretase inhibitors on angiogenesis and tumor growth. Both gamma and beta-secretase inhibitors tested reduced endothelial cell proliferation without inducing cytotoxicity, inhibited the formation of capillary structures in vitro, and inhibited the sprouting of microvascular growth in the rat aortic ring model of angiogenesis. Furthermore, they effectively inhibit the growth and angiogenesis of human glioblastoma and human lung adenocarcinoma tumors xenografted into nude mice.

Application of β-and γ-Secretase Inhibitors

Many studies have shown that presenilin may be gamma-secretase, although this remains to be confirmed. Inhibition of β- and γ-secretase, or stimulation of α-secretase, is a reasonable strategy for AD treatment intervention. A series of data suggest that γ and β-secretase play important roles in angiogenesis, and that inhibitors of γ and β-secretase can constitute a new class of anti-angiogenic and anti-tumor compounds.

References

1. Wong, G. T., Manfra, D., Poulet, F. M., Zhang, Q., Josien, H., Bara, T., ... & Zhang, L. (2004). Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. Journal of Biological Chemistry, 279(13), 12876-12882.
2. Seiffert, D., Bradley, J. D., Rominger, C. M., Rominger, D. H., Yang, F., Meredith, J. E., ... & Higaki, J. N. (2000). Presenilin-1 and-2 are molecular targets for γ-secretase inhibitors. Journal of Biological Chemistry, 275(44), 34086-34091.
3. Paris, D., Quadros, A., Patel, N., DelleDonne, A., Humphrey, J., & Mullan, M. (2005). Inhibition of angiogenesis and tumor growth by β and γ-secretase inhibitors. European journal of pharmacology, 514(1), 1-15.