The mutation at codons 670/671 of -amyloid precursor protein (PP) dramatically elevates amyloid -protein (A) production. Since increased A may be responsible for the disease phenotype identified from a Swedish kindred with familial Alzheimer's disease, evaluation of the cellular mechanism(s) responsible for the enhanced A release may suggest potential therapies for Alzheimer's disease. In this study, we analyzed Chinese hamster ovary cells stably transfected with either wild type PP (PP-wt) or ``Swedish'' mutant PP (PP-sw) for potential differences in PP processing. We confirmed that increased amounts of A and a -secretase-cleaved COOH-terminally truncated soluble PP (PP) were secreted from PP-sw cells. As shown previously for PP-wt cells, A was released more slowly than the secretion of PP from surface-labeled PP-sw cells, indicating that endocytosis of cell surface PP is one source of A production. In contrast, by [S]methionine metabolic labeling, the rates of A and PP release were virtually identical for both cell lines. In addition, the identification of intracellular PP and A shortly after pulse labeling suggests that A is produced in the secretory pathway. Interestingly, more A was present in medium from PP-sw cells than PP-wt cells after either cell surface iodination or [S]methionine labeling, indicating that PP-sw cells have enhanced A release in both the endocytic and secretory pathways. Furthermore, a variety of drug treatments known to affect protein processing similarly reduced A release from both PP-wt and PP-sw cells. Taken together, the data suggest that the processing pathway for PP is similar for both PP-wt and PP-sw cells and that increased A production by PP-sw cells arises from enhanced cleavage of mutant PP by -secretase, the as-yet unidentified enzyme(s) that cleaves at the NH terminus of A.

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