title: Differential effects of the swedish mutant amyloid precursor protein on beta-amyloid accumulation and secretion in neurons and nonneuronal cells.
abstract: 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.
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Forman
authors.forename: D G
authors.initials: DG
authors.lastname: Cook
authors.forename: S
authors.initials: S
authors.lastname: Leight
authors.forename: R W
authors.initials: RW
authors.lastname: Doms
authors.forename: V M
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor