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ASP1 (BACE2) Cleaves the Amyloid Precursor Protein at the β-Secretase Site

https://doi.org/10.1006/mcne.2000.0884Get rights and content

Abstract

Sequential proteolytic processing of the Amyloid Precursor Protein (APP) by β- and γ-secretases generates the 4-kDa amyloid (Aβ) peptide, a key component of the amyloid plaques seen in Alzheimer's disease (AD). We and others have recently reported the identification and characterisation of an aspartic proteinase, Asp2 (BACE), as β-secretase. Here we describe the characterization of a second highly related aspartic proteinase, Asp1 as a second β-secretase candidate. Asp1 is expressed in brain as detected at the mRNA level and at the protein level. Transient expression of Asp1 in APP-expressing cells results in an increase in the level of β-secretase-derived soluble APP and the corresponding carboxy-terminal fragment. Paradoxically there is a decrease in the level of soluble Aβ secreted from the cells. Asp1 colocalizes with APP in the Golgi/endoplasmic reticulum compartments of cultured cells. Asp1, when expressed as an Fc fusion protein (Asp1-Fc), has the N-terminal sequence ALEP… , indicating that it has lost the prodomain. Asp1-Fc exhibits β-secretase activity by cleaving both wild-type and Swedish variant (KM/NL) APP peptides at the β-secretase site.

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