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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.
Figure 1. Conserved Regions of the Amyloid-β Precursor Protein Gene Family. Schematic representations of the five members of the Amyloid-β Precursor Protein (AβPP) gene family show multiple conserved domains: N-Terminal Signal peptide (NTS), growth factor-like domain (GFLD), heparin binding domain (Hep), copper binding domain (Cu), zinc binding domain (Zn), an acidic amino-acid rich region (D/E), collagen binding domain (Col), a basolateral sorting signal (BLS), and a clathrin-binding internalization signal domain (YENPTY). Certain members of the gene family also contain a Kunitz-protease inhibitor domain (KPI), the amyloid-β forming region (βA4), an OX-2 domain (diagonal hashmarks), a putative collagen binding domain (horizontal white hashmarks), and/or a glutamine and serine-rich region (Q/S).
Figure 2. Phylogenetic Relationships of 103 members of the Amyloid-β Precursor Protein Gene Family. Shown are: (a) Phylogram showing the evolutionary relationships among the nucleotide sequences of the AβPP gene family; (b) Phylogram for the corresponding protein sequences. Trees were generated by maximum parsimony methods. Scale bars indicate character changes contributing to branch lengths.
Figure 3. Synapomorphic Character Frequencies for the Amyloid-β Precursor Protein Gene Family. Histogram of synapomorphic frequency generated for the whole gene family above the aligned amino acid character map. The colors of the character map were arbitrarily assigned by Mesquite. Lack of a colored line indicates a gap in the aligned sequences. The five major branches of the AβPP phylogenetic tree are indicated to the left of the map. The histogram is binned at 5 residues and scaled as a percentage.
Figure 4. Synapomorphic Frequencies Correspond to Conserved Sequences in the Amyloid-β Precursor Protein Gene Family. Histograms of synapomorphic frequency generated for each major branch of the gene family above the representative schematic for each member and the amino acid character map. The colors of the character map were arbitrarily assigned by Mesquite. Lack of a colored line indicates a gap in the aligned sequences. Relevant taxonomic/cladistic classifications are indicated to the left of the maps. (a) APL-1; (b) APPL-1; (c) AbPP; (d) APLP-2; and (e) APLP-1 histograms are binned at 5 residues and scaled as percentages. Descriptions of the schematic regions are found in Figure 1.
Figure 5. Amyloidogenic Potential in the Amyloid-β Sequence. Aligned representative amino acid sequences for the regions corresponding to exons 16 – 17 of human AβPP. Sequences tested are marked with boxes. Residues with AmylPred consensus and PASTA energies < − 4 are in red; residues with AmylPred consensus and PASTA energies between – 3 and – 4 are in blue. Known secretase cleavage sites are marked by arrows.
Figure 6. Amyloid Potential in Invertebrate Amyloid-β Sequence. Plots of probability of aggregation and stabilization of β-fibrils for each amino acid residue from PASTA for representative species. (a) Hydra magnipapillata, (b) Nematostella vectensis, (c) Caenorhabditis elegans, (d) Trichinella spiralis, (e) Neohelice granulata, (f) Daphnia pulex, (g) Drosophila melanogaster, (h) Aedes aegypti, (i) Loligo pealei, (j) Aplysia californica, (k) Stronglyocentrotus pupuratus, and (l) Branchiostoma floridae. Residues with PASTA energies < − 4 and AmylPred consensus are marked with a black line; residues with PASTA energies between – 3 and – 4 and AmylPred consensus are marked with a grey line.
Figure 7. Amyloid Potential in Vertebrate Amyloid-β Sequence. Plots of probability of aggregation and stabilization of β-fibrils for each amino acid residue from PASTA for representative species. (a) Narke japonica AβPP, (b) Danio rerio AβPP, (c) Homo sapiens AβPP, (d) Mus musculus AβPP, (e) Danio rerio APLP2, (f) Homo sapiens APLP2, (g) Xenopus laevis APLP1, (h) Monodelphis domestica APLP1, and (i) Homo sapiens APLP1. Residues with PASTA energies < − 4 and AmylPred consensus are marked with a black line; residues with PASTA energies between – 3 and – 4 and AmylPred consensus are marked with a grey line.
Figure 8. Evolutionary Relationship of Amyloid-β Formation Potential. Phylogram of the protein sequence for the AβPP family color-coded by prediction of Amyloid-β formation. Red: High potential (PASTA energies < − 4 and AmylPred consensus); Blue: Low potential (PASTA energies between – 3 and – 4 and AmylPred consensus); Black: No potential. Species with unique sequences demonstrating potential for Amyloid-β formation are labeled.
Barrachina,
Amyloid-beta deposition in the cerebral cortex in Dementia with Lewy bodies is accompanied by a relative increase in AbetaPP mRNA isoforms containing the Kunitz protease inhibitor.
2005, Pubmed
Barrachina,
Amyloid-beta deposition in the cerebral cortex in Dementia with Lewy bodies is accompanied by a relative increase in AbetaPP mRNA isoforms containing the Kunitz protease inhibitor.
2005,
Pubmed
Beach,
Physiologic origins of age-related beta-amyloid deposition.
2008,
Pubmed
Brack,
Beta structures of alternating polypeptides and their possible prebiotic significance.
1975,
Pubmed
Bush,
The amyloid precursor protein of Alzheimer's disease is released by human platelets.
1990,
Pubmed
Carmine-Simmen,
Neurotoxic effects induced by the Drosophila amyloid-beta peptide suggest a conserved toxic function.
2009,
Pubmed
Chernoff,
Amyloidogenic domains, prions and structural inheritance: rudiments of early life or recent acquisition?
2004,
Pubmed
Coulson,
What the evolution of the amyloid protein precursor supergene family tells us about its function.
2000,
Pubmed
Dayan,
Comparative neuropathology of ageing. Studies on the brains of 47 species of vertebrates.
1971,
Pubmed
Edgar,
MUSCLE: multiple sequence alignment with high accuracy and high throughput.
2004,
Pubmed
Fernandez-Escamilla,
Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins.
2004,
Pubmed
Finch,
The evolution of Alzheimer disease, the reproductive schedule, and apoE isoforms.
1999,
Pubmed
Flood,
A transgenic rat model of Alzheimer's disease with extracellular Abeta deposition.
2009,
Pubmed
Frousios,
Amyloidogenic determinants are usually not buried.
2009,
Pubmed
Galloway,
beta-amyloid or its precursor protein is found in epithelial cells of the small intestine and is stimulated by high-fat feeding.
2007,
Pubmed
Greenwald,
Biology of amyloid: structure, function, and regulation.
2010,
Pubmed
Guo,
APP physiological and pathophysiological functions: insights from animal models.
2012,
Pubmed
Hamodrakas,
Protein aggregation and amyloid fibril formation prediction software from primary sequence: towards controlling the formation of bacterial inclusion bodies.
2011,
Pubmed
Hansel,
Increased expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation.
2003,
Pubmed
Hardy,
The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.
2002,
Pubmed
Heber,
Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members.
2000,
Pubmed
Herzog,
Biological roles of APP in the epidermis.
2004,
Pubmed
Hogl,
Determination of the proteolytic cleavage sites of the amyloid precursor-like protein 2 by the proteases ADAM10, BACE1 and γ-secretase.
2011,
Pubmed
Hornsten,
APL-1, a Caenorhabditis elegans protein related to the human beta-amyloid precursor protein, is essential for viability.
2007,
Pubmed
Huson,
Dendroscope: An interactive viewer for large phylogenetic trees.
2007,
Pubmed
Inge-Vechtomov,
Biological roles of prion domains.
2007,
Pubmed
Ionov,
Amyloid-beta production in aged guinea pigs: atropine-induced enhancement is reversed by naloxone.
2010,
Pubmed
Jacobsen,
Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors.
2009,
Pubmed
Joachim,
Amyloid beta-protein deposition in tissues other than brain in Alzheimer's disease.
1989,
Pubmed
Jonsson,
A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.
2012,
Pubmed
Joshi,
Amyloid precursor protein is required for convergent-extension movements during Zebrafish development.
2009,
Pubmed
Kang,
The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor.
NULL,
Pubmed
Kotzbauer,
Pathologic accumulation of α-synuclein and Aβ in Parkinson disease patients with dementia.
2012,
Pubmed
Kuo,
Elevated abeta42 in skeletal muscle of Alzheimer disease patients suggests peripheral alterations of AbetaPP metabolism.
2000,
Pubmed
Lee,
Amyloid precursor protein expression is upregulated in adipocytes in obesity.
2008,
Pubmed
Li,
Genetic dissection of the amyloid precursor protein in developmental function and amyloid pathogenesis.
2010,
Pubmed
Liang,
Neuronal gene expression in non-demented individuals with intermediate Alzheimer's Disease neuropathology.
2010,
Pubmed
Link,
C. elegans models of age-associated neurodegenerative diseases: lessons from transgenic worm models of Alzheimer's disease.
2006,
Pubmed
Maldonado,
Timing of neurodegeneration and beta-amyloid (Abeta) peptide deposition in the brain of aging kokanee salmon.
2002,
Pubmed
Miklós,
Positive evolutionary selection of an HD motif on Alzheimer precursor protein orthologues suggests a functional role.
2012,
Pubmed
Minogue,
gamma-secretase processing of APLP1 leads to the production of a p3-like peptide that does not aggregate and is not toxic to neurons.
2009,
Pubmed
Nakayama,
Cerebral amyloid angiopathy in an aged great spotted woodpecker (Picoides major).
1999,
Pubmed
Nikolaev,
APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
2009,
Pubmed
Poeck,
Analysis of amyloid precursor protein function in Drosophila melanogaster.
2012,
Pubmed
Putnam,
Sea anemone genome reveals ancestral eumetazoan gene repertoire and genomic organization.
2007,
Pubmed
Ronquist,
MrBayes 3: Bayesian phylogenetic inference under mixed models.
2003,
Pubmed
Rosenberg,
The molecular and genetic basis of AD: the end of the beginning: the 2000 Wartenberg lecture.
2000,
Pubmed
Selkoe,
Conservation of brain amyloid proteins in aged mammals and humans with Alzheimer's disease.
1987,
Pubmed
Sinha,
Cellular mechanisms of beta-amyloid production and secretion.
1999,
Pubmed
Song,
Knockdown of amyloid precursor protein in zebrafish causes defects in motor axon outgrowth.
2012,
Pubmed
Thinakaran,
Amyloid precursor protein trafficking, processing, and function.
2008,
Pubmed
Trovato,
The PASTA server for protein aggregation prediction.
2007,
Pubmed
Trovato,
Insight into the structure of amyloid fibrils from the analysis of globular proteins.
2006,
Pubmed
Turjak,
A method for measuring support for synapomorphy using character state distributions on phylogenetic trees.
2012,
Pubmed
Walsh,
The APP family of proteins: similarities and differences.
2007,
Pubmed
Whelan,
A general empirical model of protein evolution derived from multiple protein families using a maximum-likelihood approach.
2001,
Pubmed
Xu,
Protease nexin-2/amyloid beta-protein precursor limits cerebral thrombosis.
2005,
Pubmed
Yamada,
Cerebral amyloid angiopathy.
2012,
Pubmed
Yanagida,
The 28-amino acid form of an APLP1-derived Abeta-like peptide is a surrogate marker for Abeta42 production in the central nervous system.
2009,
Pubmed
von Koch,
Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice.
1997,
Pubmed
