EXPRESSION OF THE APP GENE FAMILY IN BRAIN-CELLS, BRAIN-DEVELOPMENT AND AGING

The Alzheimer's beta A4-amyloid protein precursor (APP) and the APP-li ke proteins (APLPs) are transmembrane glycoproteins with a similar mod ular domain structure. Alternatively spliced exons found in both genes comprise a Kunitz protease inhibitor domain encoding exon, and anothe r exon within the divergent regions adjacent to the transmembrane doma in, i.e. exon 15 of the APP gene and an exon encoding 12 residues in A PLP2. Omission of the latter exons in L-APP and L-APLP2 isoforms, resp ectively, generates a functional recognition sequence for xylosyltrans ferase-mediated addition of glycosaminoglycans and proteoglycan format ion. In this paper, we summarize our analyses of the regulated express ion of these alternatively spliced exons in APP and APLP2 in primary c ultured rat brain cells, rat brain development and aging. In conjuncti on with additional data for the human brain, these data provide import ant clues for understanding the functional significance of alternative splicing and glycosylation in APP biology. On the basis of recent res ults showing a higher amyloidogenicity of exon 15 encoding APP than L- APP isoforms, we further discuss the potential significance of the low levels of LAPP in neurons for the susceptibility of the brain towards Alzheimer's disease.