Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration
Wei Xu, … , William C. Mobley, Chengbiao Wu
Wei Xu, … , William C. Mobley, Chengbiao Wu
Published April 11, 2016
Citation Information: J Clin Invest. 2016;126(5):1815-1833. https://doi.org/10.1172/JCI82409.
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Research Article Neuroscience

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

Wei Xu, April M. Weissmiller, Joseph A. White II, Fang Fang, Xinyi Wang, Yiwen Wu, Matthew L. Pearn, Xiaobei Zhao, Mariko Sawa, Shengdi Chen, Shermali Gunawardena, Jianqing Ding, William C. Mobley, Chengbiao Wu

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Figure 1

Rab5+ early endosomes were enlarged in primary BFCNs of Ts65Dn mice.

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Rab5+ early endosomes were enlarged in primary BFCNs of Ts65Dn mice. (A)...
(A) Representative images of primary BFCNs (DIV7) were costained for the cholinergic neuronal marker ChAT (red) and the NGF receptor TrkA (green). DIC and merged images are also shown. Scale bars: 10 μm. (B) Representative images are shown for Rab5 staining of BFCNs from Ts65Dn (right) and 2N littermates (left). The sizes of Rab5+ puncta in BFCNs from Ts65Dn and 2N littermates were quantified using ImageJ. Insets: Zoom-in (×2) images of selected areas. Scale bar: 15 μm. (C) Measurement of Rab5+ puncta in B. The average area was 0.468 μm2 (n = 308) for Ts65Dn, 0.295 μm2 (n = 509) for 2N. The measurements were from 3 experiments, with 20–30 cells analyzed each time. (D) The size distribution of Rab5+ puncta in BFCNs from Ts65Dn mice showed a shift from smaller to larger binned areas in comparison to those from 2N littermates. All data represent mean ± SEM (n = 3), and P values were calculated using Student’s t test. n.s., nonsignificant.