APP and Alzheimer disease: It is also revealed that Rab5 overactivation induces increased glycogen synthase kinase-3β (GSK-3β) activation and tau hyperphosphorylation in cortical neurons (Pensalfini et al., 2020), suggesting that exuberant APP signaling in endosomes deteriorates cytoskeletal organization leading to the accumulation of hyperphosphorylated tau, one of the pathological hallmarks of AD.