title: Origins of amyloid-β.
abstract: BACKGROUND
  Amyloid-β plaques are a defining characteristic of Alzheimer Disease. However, Amyloid-β deposition is also found in other forms of dementia and in non-pathological contexts. Amyloid-β deposition is variable among vertebrate species and the evolutionary emergence of the amyloidogenic property is currently unknown. Evolutionary persistence of a pathological peptide sequence may depend on the functions of the precursor gene, conservation or mutation of nucleotides or peptide domains within the precursor gene, or a species-specific physiological environment.
  
  
  RESULTS
  In this study, we asked when amyloidogenic Amyloid-β first arose using phylogenetic trees constructed for the Amyloid-β Precursor Protein gene family and by modeling the potential for Amyloid-β aggregation across species in silico. We collected the most comprehensive set of sequences for the Amyloid-β Precursor Protein family using an automated, iterative meta-database search and constructed a highly resolved phylogeny. The analysis revealed that the ancestral gene for invertebrate and vertebrate Amyloid-β Precursor Protein gene families arose around metazoic speciation during the Ediacaran period. Synapomorphic frequencies found domain-specific conservation of sequence. Analyses of aggregation potential showed that potentially amyloidogenic sequences are a ubiquitous feature of vertebrate Amyloid-β Precursor Protein but are also found in echinoderm, nematode, and cephalochordate, and hymenoptera species homologues.
  
  
  CONCLUSIONS
  The Amyloid-β Precursor Protein gene is ancient and highly conserved. The amyloid forming Amyloid-β domains may have been present in early deuterostomes, but more recent mutations appear to have resulted in potentially unrelated amyloid forming sequences. Our results further highlight that the species-specific physiological environment is as critical to Amyloid-β formation as the peptide sequence.
authors.affiliation: Center for Clinical and Translational Science, University of Vermont, Given Courtyard N309, 89 Beaumont Avenue, Burlington, VT 05405, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Tharp
authors.forename: Indra Neil
authors.initials: IN
authors.lastname: Sarkar
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D019143:Evolution, Molecular; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D010802:Phylogeny; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor