SPECIFIC PATTERNS OF AMYLOID BETA-PROTEIN PRECURSOR ISOFORM SECRETIONAND PROTEOLYSIS IN CULTURED HUMAN-CELLS

A characteristic neuropathologic feature of Alzheimer's disease in an abundance of brain-localized neuritic plaques. These plaques are ident ified as areas of degenerating nerve terminals surrounding cores of ag gregated and insoluble fibrils of amyloid beta-protein (A beta). A bet a is generated by proteolytic cleavage of a large precursor protein, t he amyloid beta-protein precursor (A beta PP). In this study, soluble A beta PPs (sA beta PPs) secreted by human cell lines originating from different tissues were characterized. Various human cell types were s hown to secrete different characteristic isoforms of A beta PP. Periph eral cells (i.e., fibroblasts and keratinocytes) secreted only the sol uble derivative of the 770-amino acid isoform (sA beta PP770). In cont rast, cells derived from the central and peripheral nervous system (i. e., neuroblastoma and glioblastoma) secreted the soluble derivative of the 751-amino acid isoform (sA beta PP751), while the 695-amino acid isoform (sA beta PP695) was secreted exclusively by neuronal-type cell s. We have also detected proteolysis of both sA beta PP751 and sA beta PP770 that results in cleavage of the amide bond at Arg(301)-Ala(302) . This bond is located within the reactive center of the Kunitz protea se inhibitor (KPI) domain of the sA beta PP751 and sA beta PP770 isofo rms, which suggests that this proteolytic event is associated with a d istinct catabolic pathway for the KPI-containing A beta PP isoforms.