title: Asynchronous evolutionary origins of Aβ and BACE1.
abstract: 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.
authors.affiliation: Department of Biology, Kalamazoo College, Kalamazoo, MI.
authors.forename: D Blaine
authors.initials: DB
authors.lastname: Moore
authors.forename: Madelyn A
authors.initials: MA
authors.lastname: Gillentine
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Botezatu
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Wilson
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Benson
authors.forename: James A
authors.initials: JA
authors.lastname: Langeland
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000235:genetics*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019143:Evolution, Molecular; D006801:Humans; D064175:Lancelets / Q000235:genetics; D008969:Molecular Sequence Data; D010802:Phylogeny; D059748:Proteolysis
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: APP; Amyloid beta; BACE; evolution