Origins of amyloid-β

Background: Amyloid-beta plaques are a defining characteristic of Alzheimer Disease. However, Amyloid-beta deposition is also found in other forms of dementia and in non-pathological contexts. Amyloid-beta 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-beta first arose using phylogenetic trees constructed for the Amyloid-beta Precursor Protein gene family and by modeling the potential for Amyloid-beta aggregation across species in silico. We collected the most comprehensive set of sequences for the Amyloid-beta 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-beta 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-beta Precursor Protein but are also found in echinoderm, nematode, and cephalochordate, and hymenoptera species homologues. Conclusions: The Amyloid-beta Precursor Protein gene is ancient and highly conserved. The amyloid forming Amyloid-beta 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-beta formation as the peptide sequence.