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Neuromol Med (2010) 12:112 DOI 10.1007/s12017-009-8104-z
REVIEW PAPER
An Overview of APP Processing Enzymes and Products
Vivian W. Chow Mark P. Mattson
Philip C. Wong Marc Gleichmann
Received: 4 September 2009 / Accepted: 6 November 2009 / Published online: 24 November 2009 US Government 2009
Abstract The generation of amyloid b-peptide (Ab) by enzymatic cleavages of the b-amyloid precursor protein (APP) has been at the center of Alzheimers disease (AD) research. While the basic process of b- and c-secretase-mediated generation of Ab is text book knowledge, new aspects of Ab 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 Ab 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.
Keywords Amyloid beta a-secretase b-secretase
c-secretase APP AICD
Introduction
Excess amyloid b-peptide (Ab) is believed to be a main contributor to the dysfunction and degeneration of neurons that occurs in Alzheimers disease (AD) (see Thinakaran and Koo, 2008 for review). Ab is a 3843 amino acid peptide that is derived from the b-amyloid precursor protein (APP) through sequential cleavages by b- and c-secretase enzyme activities. The cleavage site for another APP processing enzyme, a-secretase, lies within the Ab sequence and, thus, precludes Ab formation. The amino-terminal fragment generated through a- or b-secretase is called secreted APP (sAPP) a or b, respectively. The carboxy-terminal fragments (CTF) generated by a- and bsecretase are called CTF83 and CTF99, respectively.
c-Secretase cleavage of CTF83 and CTF99 will result in the generation of p3 and Ab, respectively, as well as the amino-terminal APP intracellular domain (AICD) (Fig. 1).
a-Secretase activity is mediated by one or more enzymes from the family of disintegrin and metalloproteinase domain proteins (ADAM), with ADAM 9, 10, 17, and 19 being the most likely candidates (Fahrenholz et al. 2000; Asai et al. 2003; Tanabe et al....