Asynchronous evolutionary origins of A? and BACE1.

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

SUBMITTER: Moore DB 

PROVIDER: S-EPMC3935185 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature