Review
What the evolution of the amyloid protein precursor supergene family tells us about its function

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Abstract

The Alzheimer’s disease amyloid protein precursor (APP) gene is part of a multi-gene super-family from which sixteen homologous amyloid precursor-like proteins (APLP) and APP species homologues have been isolated and characterised. Comparison of exon structure (including the uncharacterised APL-1 gene), construction of phylogenetic trees, and analysis of the protein sequence alignment of known homologues of the APP super-family were performed to reconstruct the evolution of the family and to assess the functional significance of conserved protein sequences between homologues. This analysis supports an adhesion function for all members of the APP super family, with specificity determined by those sequences which are not conserved between APLP lineages, and provides evidence for an increasingly complex APP superfamily during evolution. The analysis also suggests that Drosophila APPL and Caenorhabdotids elegans APL-1 may be a fourth APLP lineage indicating that these proteins, while not functional homologues of human APP, are similarly likely to regulate cell adhesion. Furthermore, the βA4 sequence is highly conserved only in APP orthologues, strongly suggesting this sequence is of significant functional importance in this lineage.

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.

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    Present address: NEHI, PO RMH, Parkville, Victoria, Vic 3050, Australia

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