Identification of a novel aspartic protease (Asp 2) as beta-secretase

I Hussain, D Powell, D R Howlett, D G Tew, T D Meek, C Chapman, I S Gloger, K E Murphy, C D Southan, D M Ryan, T S Smith, D L Simmons, F S Walsh, C Dingwall, G Christie

Research output: Contribution to journalArticlepeer-review

Abstract

The Alzheimer's disease beta-amyloid peptide (Abeta) is produced by excision from the type 1 integral membrane glycoprotein amyloid precursor protein (APP) by the sequential actions of beta- and then gamma-secretases. Here we report that Asp 2, a novel transmembrane aspartic protease, has the key activities expected of beta-secretase. Transient expression of Asp 2 in cells expressing APP causes an increase in the secretion of the N-terminal fragment of APP and an increase in the cell-associated C-terminal beta-secretase APP fragment. Mutation of either of the putative catalytic aspartyl residues in Asp 2 abrogates the production of the fragments characteristic of cleavage at the beta-secretase site. The enzyme is present in normal and Alzheimer's disease (AD) brain and is also found in cell lines known to produce Abeta. Asp 2 localizes to the Golgi/endoplasmic reticulum in transfected cells and shows clear colocalization with APP in cells stably expressing the 751-amino-acid isoform of APP.

Original languageEnglish
Pages (from-to)419-27
Number of pages9
JournalMolecular and Cellular Neuroscience
Volume14
Issue number6
DOIs
Publication statusPublished - Dec 1999

Keywords

  • Alzheimer Disease
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor
  • Animals
  • Aspartic Acid Endopeptidases
  • COS Cells
  • Cathepsin D
  • Cell Line
  • Cell Membrane
  • Endopeptidases
  • Female
  • Hippocampus
  • Humans
  • Middle Aged
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Papain
  • Recombinant Proteins
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Transfection

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