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

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... wt) or "Swedish" mutant ␤PP (␤PPsw) for potential differences in ␤PP processing. We confirmed that increased amounts of A␤ and a ␤-secretasecleaved COOH-terminally truncated soluble ␤PP (␤PP s ) were secreted from ␤PP-sw cells. As shown previously for ␤PP-wt cells, A␤ was released more slowly than the secretion of ␤PP s from surface-labeled ␤PP-sw cells, indicating that endocytosis of cell surface ␤PP is one source of A␤ production. In contrast, by [ 35 S]methionine metabolic labeling, the rates of A␤ and ␤PP s release were virtually identical for both cell lines. In addition, the identification of intracellular ␤PP s 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 [ 35 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 2 terminus of A␤.