ReviewWhat the evolution of the amyloid protein precursor supergene family tells us about its function
Section snippets
The amyloid protein precursor
Alzheimer’s disease is a common pathological process affecting the elderly, causing progressive loss of cognition. The morphologic characteristics include amyloid deposited as amyloid plaques, neurofibrillary tangles, and amyloid congophillic angiopathy. The major constituent of the amyloid is a hydrophobic peptide (βA4 or Aβ) which is derived by proteolysis from a large membrane spanning precursor protein, the amyloid protein precursor (APP).
While the etiology of Alzheimer’s disease remains
The APP gene family
The human APP cDNA was first cloned in 1987 (Goldgaber et al., 1987, Kang et al., 1987, Robakis et al., 1987) and other homologous genes were identified soon after (see Table 1 for a full list of identified homologues). cDNA sequences for APP homologues have been published for monkey, rat, mouse, frog (Xenopus levis), two species of puffer fish (Fugu rubries and Tetradon fluviatis), and electric ray (Narke japonica). We have also cloned a partial chicken APP cDNA which extends that previously
Phylogenetic analysis using three conserved protein domains
The usefulness of invertebrate animals as model systems for studying the functions of molecules, such as those involved in neuronal development or signal transduction pathways, is well documented; an ever increasing number of proteins charaterised initially in invertebrate animals have been found to have functionally homologous roles in mammalian pathways. However, the relationship of the invertebrate proteins APPL and APL-1 to the human APP/APLP proteins is debatable. The reconstruction of the
Proteins from each APLP lineage have adhesion properties
Assessment of conserved motifs found by protein sequence alignment (Table 2) support the proposal that APL-1 and APPL have functional differences from each other as well as from APP, while all lineages retain some regions of homology which extend over the entire super-family (Fig. 3). An indication of the limited functional similarity of all APP homologues, as suggested by the family homology, was demonstrated in experiments where human APP recovered, albeit partially, the behavioral phenotype
Sequence differences between lineages regulate functional differences
Of the functional domains conserved throughout the family, a majority appear to effect adhesion properties and have been retained in all lineages. The domains conserved both in exon structure and sequence presumably convey advantageous properties i.e. functionality of the protein, to the organism. Thus, there is strong sequence evidence that the normal function of APP is to regulate cell–cell or cell–substrate interactions and this is true for all paralogues. Sequence changes that have resulted
Summary
The analysis of protein sequences for all members of the APP supergene family, together with phylogenetic and experimental data, strongly argue that the normal functional role of APP relates to cell–cell or cell–substrate adhesion. Furthermore, the evidence suggests that all members of the super family have similar functional properties. However, while partially redundant, the function of APP will be different to functions of paralogues APLP1, APLP2, APPL and APL-1. This is particularly obvious
Acknowledgements
We thank Dr Gary Saunders for assistance with the phylogenetic program. This study is supported in part from grants from the National Health and Medical Research Council of Australia. KB is supported by the Deutsche Forschungsgemeinschaft and the Bundesminesterium für Forschung und Technologie.
References (86)
- et al.
Beta-amyloid stimulates glial cells in vitro to produce growth factors that accumulate in senile plaques in Alzheimer’s disease
Brain Res.
(1992) - et al.
Regulation of amyloid protein precursor (APP) binding to collagen and mapping of the binding sites on APP and collagen type I
J. Biol. Chem.
(1996) - et al.
Evolutionary origins and maintenance of redundant gene expression during metazoan development
Trends Genet.
(1997) - et al.
Down-regulation of the amyloid protein precursor of Alzheimer’s disease by antisense oligonucleotides reduces neuronal adhesion to specific substrata
Brain Res.
(1997) - et al.
The amyloid beta protein precursor or proteinase nexin II from mouse is closer related to its human homolog than previously reported
Biochim. Biophys. Acta
(1991) - et al.
The beta A4 amyloid precursor protein binding to copper
FEBS Lett.
(1994) - et al.
Alzheimer’s disease amyloid peptide is encoded by two exons and shows similarity to soybean trypsin inhibitor
Biochem. Biophys. Res. Commun.
(1989) - et al.
Conservation of the sequence of the Alzheimer’s disease amyloid peptide in dog, polar bear and five other mammals by cross-species polymerase chain reaction analysis
Brain Res. Mol. Brain Res.
(1991) - et al.
Selective localization of amyloid precursor-like protein 1 in the cerebral cortex postsynaptic density
Brain Res. Mol. Brain Res.
(1995) - et al.
beta-Amyloid protein induces platelet aggregation and supports platelet adhesion
Biochem. Biophys. Res. Commun.
(1994)
Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene
Neuron
The amyloid precursor protein is developmentally regulated and correlated with synaptogenesis
Dev. Biol.
Interaction between the zinc (II) and the heparin binding site of the Alzheimer’s disease beta A4 amyloid precursor protein (APP)
FEBS Lett.
cDNA sequence of zebrafish (Brachydanio rerio) translation elongation factor-1 alpha: molecular phylogeny of eukaryotes based on elongation factor-1 alpha protein sequences
Biochim. Biophys. Acta
Identification of the Alzheimer beta/A4 amyloid precursor protein in clathrin-coated vesicles purified from PC12 cells
J. Biol. Chem.
A Xenopus homologue of the human beta-amyloid precursor protein: developmental regulation of its gene expression
Biochem. Biophys. Res. Commun.
Evolutionary history of the ligand-gated ion-channel superfamily of receptors
Trends Neurosci.
Chromosome 21q21 sublocalisation of gene encoding beta-amyloid peptide in cerebral vessels and neuritic (senile) plaques of people with Alzheimer disease and Down syndrome
Lancet
APP gene family: unique age-associated changes in splicing of Alzheimer’s betaA4-amyloid protein precursor
Neurobiol. Dis.
Beta A4-amyloid protein precursor mRNA isoforms without exon 15 are ubiquitously expressed in rat tissues including brain, but not in neurons
J. Biol. Chem.
Complete nucleotide and deduced amino acid sequence of rat amyloid protein precursor-like protein 2 (APLP2/APPH): two amino acids length difference to human and murine homologues
Biochim. Biophys. Acta
Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP)
J. Biol. Chem.
Alzheimer’s disease amyloid precursor protein on the surface of cortical neurons in primary culture co-localizes with adhesion patch components
Brain Res.
The amyloid precursor protein of Alzheimer’s disease is found on the surface of static but not activity motile portions of neurites
Brain Res.
Three types of amyloid protein precursor mRNA in human brain: their differential expression in Alzheimer’s disease
Biochem. Biophys. Res. Commun.
Molecular genealogy of some nematode taxa as based on cytochrome c and globin amino acid sequences
Mol. Phylogenet. Evol.
Analysis of pufferfish homologues of the AT-rich human APP gene
Gene
Identification, biogenesis, and localization of precursors of Alzheimer’s disease A4 amyloid protein
Cell
Complementary DNA for the mouse homolog of the human amyloid beta protein precursor
Biochem. Biophys. Res. Commun.
Genomic structure and chromosomal localization of the mouse CDEI-binding protein CDEBP (APLP2) gene and promoter sequences
Genomics
Genomic organization of the human amyloid beta-protein precursor gene
Gene
Characterization of the genomic structure of the mouse APLP1 gene
Genomics
Increased production of amyloid precursor protein provides a substrate for caspase-3 in dying motoneurons
J. Neurosci.
APP-collagen interaction is mediated by a heparin bridge mechanism
Mol. Chem. Neuropathol.
Beta amyloid precursor protein mediates neuronal cell–cell and cell–surface adhesion
J. Neurosci. Res.
Rapid induction of Alzheimer A beta amyloid formation by zinc
Science
Modulation of A beta adhesiveness and secretase site cleavage by zinc
J. Biol. Chem.
The amyloid beta-protein precursor and its mammalian homologues. Evidence for a zinc-modulated heparin-binding superfamily
J. Biol. Chem.
apl-1, a Caenorhabditis elegans gene encoding a protein related to the human beta-amyloid protein precursor
Proc. Natl. Acad. Sci. USA
Confidence limits on phylogenesis: an approach using the bootstrap
Evolution
Intraneuronal compartments of the amyloid precursor protein
J. Neurosci.
Transgenic Drosophila expressing human amyloid precursor protein show gamma-secretase activity and a blistered-wing phenotype
Proc. Natl. Acad. Sci. USA
Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease
Science
Cited by (0)
- 1
Present address: NEHI, PO RMH, Parkville, Victoria, Vic 3050, Australia