Asynchronous evolutionary origins of Aβ and BACE1

Mol Biol Evol. 2014 Mar;31(3):696-702. doi: 10.1093/molbev/mst262. Epub 2013 Dec 19.


Neurodegenerative plaques characteristic of Alzheimer's disease (AD) are composed of amyloid beta (Aβ) peptide, which is proteolyzed from amyloid precursor protein (APP) by β-secretase (beta-site APP cleaving enzyme [BACE1]) and γ-secretase. Although γ-secretase has essential functions across metazoans, no essential roles have been identified for BACE1 or Aβ. Because their only known function results in a disease phenotype, we sought to understand these components from an evolutionary perspective. We show that APP-like proteins are found throughout most animal taxa, but sequences homologous to Aβ are not found outside gnathostomes and the β cut site is only conserved within sarcopterygians. BACE1 enzymes, however, extend through basal chordates and as far as cnidaria. We then sought to determine whether BACE1 from a species that never evolved Aβ could proteolyze APP substrates that include Aβ. We demonstrate that BACE1 from a basal chordate is a functional ortholog that can liberate Aβ from full-length human APP, indicating BACE1 activity evolved at least 360 My before Aβ.

Keywords: APP; Amyloid beta; BACE; evolution.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / genetics*
  • Amyloid beta-Protein Precursor / chemistry
  • Amyloid beta-Protein Precursor / genetics*
  • Animals
  • Aspartic Acid Endopeptidases / chemistry
  • Aspartic Acid Endopeptidases / genetics*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Evolution, Molecular*
  • Humans
  • Lancelets / genetics
  • Molecular Sequence Data
  • Phylogeny
  • Proteolysis


  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human