The Ras-related GTP-binding protein, Rab1B, regulates early steps in exocytic transport and processing of beta-amyloid precursor protein.

The role of the Ras-related GTP-binding protein, Rab1B, in intracellular trafficking of beta-amyloid precursor protein (beta APP) was studied in cultured 293 cells. beta APP is processed via one of two alternative routes. In the major secretory pathway, beta APP is cleaved by alpha-secretase within the region comprising the beta-amyloid peptide (A beta), resulting in release of a soluble NH2-terminal exodomain (APP alpha) and a 3-kDa peptide (p3) derived from the carboxyl-terminal tail. In the alternative amyloidogenic pathway, beta APP is cleaved by beta-secretase, with the release of a truncated exodomain (APP beta) and an intact A beta peptide. When beta APP751 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 beta APP751 (108 kDa) to the mature O-glycosylated form of beta APP751 (130 kDa) in cells expressing the mutant forms of Rab1B. The block in Golgi-dependent processing of beta APP was accompanied by inhibition of secretion of APPS (APP alpha). A similar decrease in secretion of APPS (APP alpha+APP beta) was observed in cells that were coexpressing Rab1BN121I with the "Swedish" variant of beta APP751 (i.e. beta APPSW751), which undergoes increased amyloidogenic processing. Coincident with the decline in APPS secretion, the cells coexpressing beta APPSW751 with Rab1BN121I showed a 90% decrease in A beta secretion. The data indicate that Rab1B plays a key role in endoplasmic reticulum-->Golgi transport of beta APP, and that beta APP must pass through a late Golgi compartment before entering either the alpha-secretase or the amyloidogenic beta-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 beta APP transport involved in the biogenesis of A beta.