title: Amyloid precursor protein-mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration.
abstract: The endosome/lysosome pathway is disrupted early in the course of both Alzheimer's disease (AD) and Down syndrome (DS); however, it is not clear how dysfunction in this pathway influences the development of these diseases. Herein, we explored the cellular and molecular mechanisms by which endosomal dysfunction contributes to the pathogenesis of AD and DS. We determined that full-length amyloid precursor protein (APP) and its β-C-terminal fragment (β-CTF) act though increased activation of Rab5 to cause enlargement of early endosomes and to disrupt retrograde axonal trafficking of nerve growth factor (NGF) signals. The functional impacts of APP and its various products were investigated in PC12 cells, cultured rat basal forebrain cholinergic neurons (BFCNs), and BFCNs from a mouse model of DS. We found that the full-length wild-type APP (APPWT) and β-CTF both induced endosomal enlargement and disrupted NGF signaling and axonal trafficking. β-CTF alone induced atrophy of BFCNs that was rescued by the dominant-negative Rab5 mutant, Rab5S34N. Moreover, expression of a dominant-negative Rab5 construct markedly reduced APP-induced axonal blockage in Drosophila. Therefore, increased APP and/or β-CTF impact the endocytic pathway to disrupt NGF trafficking and signaling, resulting in trophic deficits in BFCNs. Our data strongly support the emerging concept that dysregulation of Rab5 activity contributes importantly to early pathogenesis of AD and DS.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: April M
authors.initials: AM
authors.lastname: Weissmiller
authors.forename: Joseph A
authors.initials: JA
authors.lastname: White
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wang
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Wu
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Pearn
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Zhao
authors.forename: Mariko
authors.initials: M
authors.lastname: Sawa
authors.forename: Shengdi
authors.initials: S
authors.lastname: Chen
authors.forename: Shermali
authors.initials: S
authors.lastname: Gunawardena
authors.forename: Jianqing
authors.initials: J
authors.lastname: Ding
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Wu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019943:Amino Acid Substitution; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D059329:Cholinergic Neurons / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004331:Drosophila melanogaster; D004705:Endocytosis; D051379:Mice; D020125:Mutation, Missense; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015398:Signal Transduction; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D020932:Nerve Growth Factor; D020696:rab5 GTP-Binding Proteins