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

Asynchronous evolutionary origins of Aβ and BACE1.

Author information

1
Department of Biology, Kalamazoo College, Kalamazoo, MI.

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.

KEYWORDS:

APP; Amyloid beta; BACE; evolution

PMID:
24361992
PMCID:
PMC3935185
DOI:
10.1093/molbev/mst262
[Indexed for MEDLINE]
Free PMC Article

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