Figure 3.

APP–βCTF mediates pathologic activation of rab5 on endosomes in AD, which leads to compromise of cholinergic neurons. A) Recruited APPL1 binds via its phosphotyrosine binding (PTB) domain to the YENPT domain of APP–βCTF. APPL1 dimerization via BAR domains facilitates vesicle curvature and binding of GTP-rab5 via the PH domain stabilizes rab5 in this activated state on endosomes. B) Rab5 hyperactivation slows endosome transport and diminishes TrkA signaling, which leads to the loss of trophic support for cholinergic neurons.