[Frontiers in Bioscience S4, 1126-1150 , January 1, 2012]

[Frontiers in Bioscience S4, 1126-1150 , January 1, 2012]

Alpha, beta-and gamma-secretases in alzheimer's disease

Roberta Epis¹, Elena Marcello¹, Fabrizio Gardoni ¹, Monica Di Luca¹

1Universita degli Studi di Milano, Department of Pharmacological Sciences, Via Balzaretti, 9, Milano, Italy

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. BACE1 (beta-site APP cleaving enzyme): 3.1. BACE1: molecular cell biology; 3.2. BACE1: different levels of regulation; 3.3. BACE1: substrates; 3.4. BACE1: functions
4. gamma-secretase: 4.1. The gamma-secretase complex; 4.2. Building gamma-secretase; 4.3. Gamma-secretase: mechanism of action; 4.4. Gamma-secretase: substrates and functions
5. Alpha-secretase: 5.1. Who is alpha-secretase?; 5.2. ADAM10; 5.3. ADAM10: substrates and functions; 5.4. ADAM10: regulation
6. Balance between amyloidogenic and non-amyloidogenic APP cleavage
7. Secretases as targets for Alzheimer's disease therapy: 7.1. BACE1 inhibition; 7.2. Gamma-secretase inhibition; 7.3. Alpha-secretase activation
8. Perspective
9. References

1. ABSTRACT

Generation of Amyloid peptide (Abeta) is at the beginning of a cascade that leads to Alzheimer's disease. Currenty, the mechanisms of Abeta generation and Abeta prevention are subject of intensive research. Amyloid precursor protein (APP), as well as beta- and gamma-secretases are the principal players involved in Abeta production, while alpha-secretase cleavage on APP prevents Abeta deposition. Inhibitors or modulators that target beta- and gamma-secretases as well as alpha-secretase activators are promising candidates for treatment of Alzheimer's disease. A deep knowledge of the secretases is required to develop disease modifying drugs that target them. The most challenging quest is to translate the growing knowledge about the cell biology of secretases and their mechanisms of action into effective therapeutics. Here, we review the main features of the secretases.