Structure and Function of Appican, The Proteoglycan Form of the Alzheimer Amyloid Precursor

Appicans are secreted and cell-associated chondroitin sulfate proteoglycans containing Alzheimer amyloid precursor protein (APP) as a core protein. Appicans are found in brain tissue and their expression in cell cultures depends on both cell type and growth conditions. In rat brain primary cell cultures appicans are mainly expressed by astroglial cells. Cellular appicans contain full-length APP and are found on the cell surface whereas secreted appicans contain proteolytically cleaved APP. Following the discovery of appicans it was shown that their core protein is the L-APP isoform which lacks exon 15 of the APP gene. Fusion of exon 14 to exon 16 creates an amino acid consensus sequence for the attachment of the glycosaminoglycan chain present in appican. Site directed mutagenesis was used to identify serine-619 of L-APP733 as the single chondroitin sulfate attachment site. C6 cells transfected with L-APP produced high levels of appican whereas C6 cells trans-fected with L-APPs/a, where serine-619 was mutated to alanine, produced no additional appican other than the endogenous one. Extracellular matrix prepared from C6 cells trans-fected with L-APP was a much better substrate for the attachment of neuro 2A neuroblastoma or pheochromocytoma PC12 cells than extracellular matrix prepared from C6 cells trans-fected with L-APPs/a suggesting that appicans function as cell adhesion molecules for neural cells. The recent cloning of new genes linked to familial Alzheimer disease offers new opportunities to investigate whether appican interacts with the familial Alzheimer disease genes and whether it plays any role in the development of this disease.