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The Ras-related GTP-binding Protein, Rab1B, Regulates Early Steps in Exocytic Transport and Processing of β-Amyloid Precursor Protein (*)

The role of the Ras-related GTP-binding protein, Rab1B, in intracellular trafficking of β-amyloid precursor protein (βAPP) was studied in cultured 293 cells. βAPP is processed via one of two alternative routes. In the major secretory pathway, βAPP is cleaved by α-secretase within the region comprising the β-amyloid peptide (Aβ), resulting in release of a soluble NH2-terminal exodomain (APPα) and a 3-kDa peptide (p3) derived from the carboxyl-terminal tail. In the alternative amyloidogenic pathway, βAPP is cleaved by β-secretase, with the release of a truncated exodomain (APPβ) and an intact Aβ peptide. When βAPP751 was coexpressed with Rab1B(wt) or dominant-negative Rab1B mutants (Rab1BN121I or Rab1BS22N) there was a marked decrease in conversion of the immature Endo-H sensitive form of βAPP751 (108 kDa) to the mature O-glycosylated form of βAPP751 (130 kDa) in cells expressing the mutant forms of Rab1B. The block in Golgi-dependent processing of βAPP was accompanied by inhibition of secretion of APPS (APPα). A similar decrease in secretion of APPS (APPα + APPβ) was observed in cells that were coexpressing Rab1BN121I with the “Swedish” variant of βAPP751 (i.e. βAPP SW751), which undergoes increased amyloidogenic processing. Coincident with the decline in APPS secretion, the cells coexpressing βAPP SW751 with Rab1BN121I showed a 90% decrease in Aβ secretion. The data indicate that Rab1B plays a key role in endoplasmic reticulum → Golgi transport of βAPP, and that βAPP must pass through a late Golgi compartment before entering either the α-secretase or the amyloidogenic β-secretase pathway. The results also suggest that mutant versions of other Rab proteins that function in different parts of the exocytic and endocytic pathways may be useful in defining the specific routes of βAPP transport involved in the biogenesis of Aβ.