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Volume 21 Issue 5, May 2016

At the earliest stage of Alzheimer's Disease, neuronal endosomes enlarge in response to overactivation of rab5, a key GTPase effector of endocytosis, evidenced in this image by anti-rab5 immunolabeling (red) of neocortical pyramidal neurons in control and AD brains (top and bottom panels, respectively). This endosome enlargement, reflecting a pathological upregulation of endocytosis, is induced by elevated levels of βCTF (β-secretase-cleaved C-terminal fragment of β-amyloid precursor protein) and is associated with altered endosome signaling and neurodegeneration in AD and in early-onset AD associated with Down syndrome. Evidence presented in Kim et al. 2015 further shows that in AD brain, APPL1 (green, middle column), a known effector of rab5, binds βCTF on rab5-positive endosomes as demonstrated by increased colocalization of APPL1 and rab5 (right column). Upon recruitment to endosomes, APPL1 also binds the active GTP form of rab5, thereby maintaining its activated state on endosomes and greatly upregulating endocytosis and endosome fusion. Among the pathological consequences shown in this study are defective endosomal retrograde transport and nuclear signaling, which contribute to AD pathogenesis and indicate the potential of endocytosis as a target of future AD therapies. For more info on this topic, please refer to the article by Kim et al on pages 707–716.

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