Differential effects of the swedish mutant amyloid precursor protein on beta-amyloid accumulation and secretion in neurons and nonneuronal cells.

Expression of the Swedish DeltaNL mutation in the beta-amyloid precursor protein (APPDeltaNL) dramatically increases Abeta generation in nonneuronal cell lines, although it is unclear whether intracellular levels of beta-amyloid (Abeta) are also elevated after APPDeltaNL expression. Furthermore, the effects of expressing APPDeltaNL in neurons on the production and secretion of Abeta-(1-40) and Abeta-(1-42) are unknown. To address these issues, we examined the generation of both intracellular and secreted Abeta-(1-40) and Abeta-(1-42) in human neuronal NT2N cells, in primary rat astrocytes, and in Chinese hamster ovary cells engineered to express wild-type APP or APPDeltaNL using a recombinant Semliki Forest virus expression system. Expression of APPDeltaNL led to a marked increase in APPbeta and the C-terminal fragment containing the entire Abeta sequence (C99) in all cells tested. However, a dramatic elevation of intracellular and secreted Abeta-(1-40) and Abeta-(1-42) was seen only in astrocytes and Chinese hamster ovary cells. The DeltaNL mutation did not cause a significant increase in intracellular or secreted Abeta-(1-40) or Abeta-(1-42) in NT2N cells. Since NT2N cells expressing APPDeltaNL accumulate much higher levels of C99 than cells expressing wild-type APP, we conclude that the rate-limiting step in Abeta production could be the further processing of C99 by gamma-secretase in these cells. These results show that the Swedish DeltaNL mutation causes nonneuronal cells to process APP via pathways more in common with the metabolism of wild-type APP in neurons.