Representative diagram showing some of the multiple components involved in Rab5 activation. Inactive GDP-bound Rab5 is present in the cytosol sequestered by GDI. In proximity of the target membrane, GDF may interact with Rab5 to facilitate GDI dissociation and Rab5 insertion into the membrane. Upon GDP dissociation, a GEF promotes GTP binding and subsequent activation of Rab5. In this active state Rab5 can interact with multiple effectors (not shown) to promote vesicle budding, trafficking, and fusion. Rab5 GTP hydrolysis is facilitated by a GAP, which converts Rab5 to its inactive GDP-bound state. Inactive rab5 can then be extracted from the membrane by GDI and recycled back to the cytosol. Inset, Under conditions promoting an increase in Rab5 expression (or transcription) or, as in the case of AD/DS, in the amyloid precursor protein (APP), rab5 undergoes hyper-activation, resulting in increased endocytosis and increased endosome fusion.