An overview of APP processing enzymes and products

Abstract

The generation of amyloid beta-peptide (A beta) by enzymatic cleavages of the beta-amyloid precursor protein (APP) has been at the center of Alzheimer's disease (AD) research. While the basic process of beta- and gamma-secretase-mediated generation of A beta is text book knowledge, new aspects of A beta and other cleavage products have emerged in recent years. Also our understanding of the enzymes involved in APP proteolysis has increased dramatically. All of these discoveries contribute to a more complete understanding of APP processing and the physiologic and pathologic roles of its secreted and intracellular protein products. Understanding APP processing is important for any therapeutic strategy aimed at reducing A beta levels in AD. In this review, we provide a concise description of the current state of understanding the enzymes involved in APP processing, the cleavage products generated by different processing patterns, and the potential functions of those cleavage products.

Figure 1

APP processing and cleavage products. The non-amyloidogenic APP processing pathway (right/blue) involves cleavages by α- and γ-secretases resulting in the generation of a long secreted form of APP (sAPPα) and C-terminal fragments (CTF 83, p3 and AICD50). The amyloidogenic APP processing pathway (left/red) involves cleavages by β- and γ-secretases resulting in the generation of a long secreted form of APP (sAPPβ), C-terminal fragments (CTF 99 and CTF 89) and Aβs. Aβ fragments oligomerize and fibrillize leading to AD pathology (left and upper panel). ex extracellular, PM plasma membrane, cyt cytosol, DR6 death receptor 6.

Figure 2

APP processing enzymes and their cleavage sites. The amino acid sequence of Aβ and the carboxyterminal adjacent region are displayed in single letter amino acid code. Red lines indicate the β and β’ cleavage site of BACE1. The blue line indicate the cleavage site for α-secretase, which belongs to the ADAM family of proteases. Purple lines indicate cleavage site for γ-secretase, which is located within the transmembrane region, as indicated by the black lines.