CHARACTERIZATION OF APPICAN, THE CHONDROITIN SULFATE PROTEOGLYCAN FORM OF THE ALZHEIMER AMYLOID PRECURSOR PROTEIN

Ln this report we focus on the characterization of appican, the chondr oitin sulfate proteoglycan form of amyloid precursor protein (APP), an d the role that it and other proteoglycans may play in AD. Appican is expressed by certain transformed cell lines of neural origin, namely C 6 cells and N2a neuroblastomas. It is detected in both human and rat b rain and in primary cultures is expressed by astrocytes, but not neuro ns. The core protein of appican has been shown to be an alternatively spliced isoform of APP, lacking exon 15 of the APP gene, originally id entified in leukocytes (L-APP). Splicing out of exon 15 results in the joining of exons 14 and 16, and formation of an Asp-Xaa-Ser-Gly conse nsus sequence for chondroitin sulfate chain attachment to serine 619 o f L-APP, which lies 16 amino acids upstream of the AP peptide sequence . Mutation of this serine residue to an alanine prevented chondroitin sulfate chain addition to the core protein. Levels of appican expressi on could be regulated by growth conditions independently of APP, sugge sting that these molecules may serve distinct physiological roles with in the cell. Morphological changes were also observed in both astrocyt ic and transformed cell cultures, that appeared to reflect changes in levels of appican expression. Preliminary data suggest that appican ma y be a strong cell adhesion molecule. Transfected C6 glioma cells over expressing appican remained attached to tissue culture dishes markedly better than either C6 cells over-expressing exon-15 containing APP or WT C6 cells. Appican-enriched extracellular matrix (ECM) was also obs erved to serve as a much better substrate for attachment of N2a neurob lastomas, pheocromocytoma PC12 cells and primary astrocytes compared t o APP enriched ECM. (C) 1996 Academic Press Limited