APP gene family: unique age-associated changes in splicing of Alzheimer's betaA4-amyloid protein precursor.
The betaA4-amyloid protein precursor (APP) is a transmembrane glycoprotein that is the source of the characteristic betaA4-amyloid deposits of Alzheimer brains. It exists in eight isoforms generated by alternative splicing of exons 7, 8 and 15, of which the L-APP mRNAs lacking exon 15 are significantly expressed in non-neuronal cells and tissues, but not in neurones. Recently, it was shown that APP is a member of a multigene family of which the amyloid precursor-like protein 2 (APLP2) is the nearest relative. Analysis of APLP2 expression revealed regulated alternative splicing of the Kunitz protease inhibitor domain (KPI, homologous to exon 7 of APP) and a non-homologous insert of 12 amino acids on the NH2-terminal side of the transmembrane domain. While expression of the KPI encoding exon of APLP2 is abundant in neurones and thus differs from APP, L-APLP2 mRNA isoforms lacking the latter, non-homologous insert show a tissue-specific expression pattern similar to that of exon 15 of APP. Comparison of alternatively spliced APP and APLP2 mRNA isoforms in rat brain regions from early post-natal and adult rats revealed significantly higher relative amounts of KPI-encoding APP isoforms in the adult rat brain and an even more pronounced augmentation of L-APP mRNAs. Both effects were not observed for APLP2. This indicates an APP-specific age-associated regulation pattern within the APP gene family which has intriguing implications for the development of Alzheimer's disease in humans.
Sandbrink
R
R
Zentrum für Molekulare Biologie Heidelberg (ZMBH), University of Heidelberg, Im Neuenheimer Feld 282, Heidelberg, D-69120, Germany.
Masters
C L
CL
Beyreuther
K
K
D000367:Age Factors; D000375:Aging / Q000235:genetics*; D017398:Alternative Splicing / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured / Q000378:metabolism; D015342:DNA Probes; D005786:Gene Expression Regulation; D008297:Male; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic
D016564:Amyloid beta-Protein Precursor; D015342:DNA Probes; D012333:RNA, Messenger