Differential effects of a Rab6 mutant on secretory versus amyloidogenic processing of Alzheimer's beta-amyloid precursor protein

The Ras-related GTP-binding protein, Rab6, is localized in late Golgi compartments where it mediates intraGolgi vesicular trafficking, Herein we report that coexpression of Alzheimer's beta-amyloid precursor protein (beta APP(751)) with a dominant-negative Rab6 mutant (Rab6(N126I)) in human embryonal kidney 293 cells causes an increase in secretion of the soluble amino-terminal exodomain (s-APP alpha) derived from non-amyloidogenic processing of beta-APP(751) by alpha-secretase, The effect was specific to Rab6(N126I), since the corresponding mutation in Rab8 (i,e, Rab8(N121I)), which has been implicated in protein transport to the plasma membrane, caused a modest reduction in s-APP alpha secretion. While Rab6(N126I) stimulated secretion of APP alpha, the accumulation of amyloid beta peptide (A beta) in the medium was either moderately reduced or unaffected, Similar differential effects of Rab6(N126I) on secretion of s-APP alpha versus A beta were observed in cell cultures that were overproducing A beta after transfection with a plasmid encoding the Swedish variant of beta APP(751). Moreover, assays of medium from the latter cultures revealed a marked increase in secretion of s-APP alpha relative to s-APP beta (the immediate product derived from cleavage of beta APP by beta-secretase), The results indicate that vesicular transport events controlled by Rab6 occur at or near a critical juncture in the trans-Golgi network where beta APP is sorted into either the constitutive alpha-secretase pathway or the amyloidogenic beta-secretase pathway.