Similar alternative splicing of a non-homologous domain in beta A4-amyloid protein precursor-like proteins.
The beta A4-amyloid protein precursor (APP) is a transmembrane glycoprotein that is the source of the characteristic beta A4-amyloid deposits found in Alzheimer brains. It is expressed in several isoforms generated by alternative splicing of exons 7, 8, and 15, of which the leukocyte-derived APP mRNAs lacking exon 15 are significantly expressed in non-neuronal tissues, but not in neurons. The recent finding of APP-like proteins prompted us to analyze alternative splicing of the nearest relative of APP, the amyloid protein precursor homologue (APPH) or amyloid precursor-like protein 2 (APLP2). We were able to show that there are two alternatively spliced inserts, i.e. the Kunitz protease inhibitor domain and a 12-amino-acid-encoding region on the NH2-terminal side of the transmembrane domain, which is part of the region of highest divergence between APP and APLP2/APPH. Analysis of the tissue-specific differential expression of the resulting four APLP2/APPH mRNA isoforms revealed that isoforms lacking the latter, non-homologous insert are highly expressed in non-neuronal tissues, but only weakly in neurons. While this resembles the tissue-specific alternative splicing of exon 15 of APP, expression of the Kunitz protease inhibitor-encoding exon of APLP2/APPH is abundant in both neuronal and non-neuronal tissues and thus differs from APP. Because of the similar regulation of alternative splicing of exon 15 of APP and the described APLP2/APPH insert, and because of structural similarities of the sequences and the predicted secondary structures, a functional homology of alternatively spliced isoforms of APP and APLP2/APPH is suggested.
Sandbrink
R
R
Center for Molecular Biology Heidelberg (ZMBH), University of Heidelberg, Germany.
Masters
C L
CL
Beyreuther
K
K
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000596:Amino Acids; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D005091:Exons; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity
C489697:APLP1 protein, human; C084104:APLP2 protein, human; D000596:Amino Acids; D016564:Amyloid beta-Protein Precursor; C078201:Aplp1 protein, mouse; C492952:Aplp2 protein, mouse; C498283:Aplp2 protein, rat; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger