Processing of β-Amyloid Precursor Protein by Cathepsin D

Abstract

The events leading to the formation of ␤-amyloid (␤A4) from its precursor (␤APP) involve proteolytic cleavages that produce the amino and carboxyl termini of ␤A4. The enzyme activities responsible for these cleavages have been termed ␤-and ␥-secretase, respectively, although these protease(s) have not been identified. Since ␤A4 is known to possess heterogeneity at both the amino and carboxyl termini, ␤-and ␥-secretases may actually be a collection of proteolytic activities or perhaps a single proteolytic enzyme with broad amino acid specificity.We investigated the role of cathepsin D in the processing of ␤APP since this enzyme has been widely proposed as a ␥-secretase candidate. 1, 2). The initial discovery of ␤A4 as a constituent in AD tissue prompted a number of investigations into the role of ␤-amyloid in this disease. The physical properties of ␤A4 combined with the genetic evidence linking mutations around the ␤A4 domain of the ␤-amyloid precursor protein (␤APP) to early onset forms of the disease (reviewed in Refs. 3 and 4) provide compelling evidence that this peptide is involved in the etiology of Alzheimer's disease. Unraveling the cellular mechanism of ␤APP processing and of ␤A4 production is, therefore, important in understanding the pathogenesis of AD. ␤A4 is formed by the proteolytic cleavage of a 695-770-amino acid integral membrane protein, the ␤APP at two distinct sites near the carboxyl terminus of this molecule. The proteolytic cleavage that generates the amino terminus of ␤A4 occurs approximately 28 residues extralumenal to the transmembrane domain of ␤APP, while that which generates the carboxyl terminus of ␤A4 takes place within the transmembrane domain. The protease activities that mediate these cleavage events are called ␤-and ␥-secretase, respectively. Cleavage at both the ␤-and ␥-secretase sites produces a soluble form of ␤A4 that is 40 amino acids long and ends at Val 40 (5); however, longer and potentially more pathogenic forms of ␤A4 that end at Ala 42 -Thr 43 , have also been identified (2, 6, 7). Whether these various forms of ␤A4 are produced by a single ␥-secretase is not known. A third major cleavage that is not involved in the formation of ␤A4 occurs within the ␤A4 domain of ␤APP and is generated by a protease activity called ␣-secretase.A number of recent studies have revealed important clues regarding the proteolytic processing of the ␤APP molecule. From these studies, two processing pathways have been proposed. The first is a constitutive secretion pathway that generates soluble forms of ␤APP, which are ultimately released by cells expressing the precursor protein (8). This pathway involves the primary proteolytic cleavage of ␤APP at the ␣-secretase site located within the ␤A4 domain (9, 10), releasing the large, soluble extracellular portion of ␤APP while simultaneously generating a 10-kDa membrane-associated ␤APP carboxyl-terminal fragment (11). This cleavage event precludes the formation of ␤A4. A minor cleavage event that also serves to liberate a soluble, albeit shorter...

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