Asynchronous Evolutionary Origins of Aβ and BACE1

Neurodegenerative plaques characteristic of Alzheimer's disease (AD) are composed of amyloid beta (A beta) peptide, which is proteolyzed from amyloid precursor protein (APP) by beta-secretase (beta-site APP cleaving enzyme [BACE1]) and gamma-secretase. Although gamma-secretase has essential functions across metazoans, no essential roles have been identified for BACE1 or A beta. 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 A beta are not found outside gnathostomes and the beta 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 A beta could proteolyze APP substrates that include A beta. We demonstrate that BACE1 from a basal chordate is a functional ortholog that can liberate A beta from full-length human APP, indicating BACE1 activity evolved at least 360 My before A beta.