Hyperactivation of RAB5 disrupts the endosomal Rab cascade leading to endolysosomal dysregulation in Down syndrome: A necessary role for increased <i>APP</i> gene dose

There is widespread disruption of the endolysosomal network in the Down syndrome (DS) brain and in the Dp16 mouse model brain. Amyloid precursor protein (APP) gene dose was necessary for increases in endosomal Rab activity and lysosomal cathepsins in both human and mouse brains. Changes in endosomal Rabs 7 and 11 were linked to increases in their guanine-nucleotide exchange factors (GEFs) and GEF/GTPase activating protein (GAP) ratios. Mechanistic studies demonstrated essential roles for the beta-C-terminal fragment (β-CTF) of APP acting through hyperactivation of RAB5 to increase early endosomal membrane binding of the GEFs for downstream endosomal Rabs. RAB5 acts as the central hub for disruptions in endolysosomal function in DS.