Asynchronous Evolutionary Origins of A and BACE1

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.