ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site

I Hussain, D J Powell, D R Howlett, G A Chapman, L Gilmour, P R Murdock, D G Tew, T D Meek, C Chapman, K Schneider, S J Ratcliffe, D Tattersall, T T Testa, C Southan, D M Ryan, D L Simmons, F S Walsh, C Dingwall, G Christie

Research output: Contribution to journalArticlepeer-review

Abstract

Sequential proteolytic processing of the Amyloid Precursor Protein (APP) by beta- and gamma-secretases generates the 4-kDa amyloid (A beta) 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 beta-secretase. Here we describe the characterization of a second highly related aspartic proteinase, Asp1 as a second beta-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 beta-secretase-derived soluble APP and the corresponding carboxy-terminal fragment. Paradoxically there is a decrease in the level of soluble A beta 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 beta-secretase activity by cleaving both wild-type and Swedish variant (KM/NL) APP peptides at the beta-secretase site.

Original languageEnglish
Pages (from-to)609-19
Number of pages11
JournalMolecular and Cellular Neuroscience
Volume16
Issue number5
DOIs
Publication statusPublished - Nov 2000

Keywords

  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor
  • Animals
  • Aspartic Acid Endopeptidases
  • Binding Sites
  • COS Cells
  • Cloning, Molecular
  • Endopeptidases
  • Female
  • Glycoproteins
  • Humans
  • Male
  • Membrane Proteins
  • Molecular Sequence Data
  • Rabbits
  • Recombinant Proteins
  • Sequence Homology, Amino Acid

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