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Open Access Highly Accessed Research article

Origins of amyloid-β

William G Tharp12 and Indra Neil Sarkar134*

Author Affiliations

1 Center for Clinical and Translational Science, University of Vermont, Given Courtyard N309, 89 Beaumont Avenue, Burlington, VT, 05405, USA

2 Division of Endocrinology, Department of Medicine, University of Vermont, Given Courtyard N309, 89 Beaumont Avenue, Burlington, VT, 05405, USA

3 Department of Microbiology and Molecular Genetics, University of Vermont, Given Courtyard N309, 89 Beaumont Avenue, Burlington, VT, 05405, USA

4 Department of Computer Science, University of Vermont, Given Courtyard N309, 89 Beaumont Avenue, Burlington, VT, 05405, USA

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BMC Genomics 2013, 14:290  doi:10.1186/1471-2164-14-290

Published: 30 April 2013

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 amyoid forming sequences. Our results further highlight that the species-specific physiological environment is as critical to Amyloid-β formation as the peptide sequence.

Keywords:
Amyloid; Alzheimer disease; Phylogenetics; In silico; Aggregation; Maximum parsimony; Bayesian inference