Title |
Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes
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Published in |
Molecular Brain, July 2015
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DOI | 10.1186/s13041-015-0129-7 |
Pubmed ID | |
Authors |
Weihao Tang, Joshua H.K. Tam, Claudia Seah, Justin Chiu, Andrea Tyrer, Sean P. Cregan, Susan O. Meakin, Stephen H. Pasternak |
Abstract |
Alzheimer's disease (AD) is characterized by the deposition of Beta-Amyloid (Aβ) peptides in the brain. Aβ peptides are generated by cleavage of the Amyloid Precursor Protein (APP) by the β - and γ - secretase enzymes. Although this process is tightly linked to the internalization of cell surface APP, the compartments responsible are not well defined. We have found that APP can be rapidly internalized from the cell surface to lysosomes, bypassing early and late endosomes. Here we show by confocal microscopy and electron microscopy that this pathway is mediated by macropinocytosis. APP internalization is enhanced by antibody binding/crosslinking of APP suggesting that APP may function as a receptor. Furthermore, a dominant negative mutant of Arf6 blocks direct transport of APP to lysosomes, but does not affect classical endocytosis to endosomes. Arf6 expression increases through the hippocampus with the development of Alzheimer's disease, being expressed mostly in the CA1 and CA2 regions in normal individuals but spreading through the CA3 and CA4 regions in individuals with pathologically diagnosed AD. Disruption of lysosomal transport of APP reduces both Aβ40 and Aβ42 production by more than 30 %. Our findings suggest that the lysosome is an important site for Aβ production and that altering APP trafficking represents a viable strategy to reduce Aβ production. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 2 | 50% |
Unknown | 2 | 50% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 50% |
Science communicators (journalists, bloggers, editors) | 1 | 25% |
Scientists | 1 | 25% |
Mendeley readers
Geographical breakdown
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Unknown | 74 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 18 | 24% |
Student > Bachelor | 13 | 18% |
Student > Master | 9 | 12% |
Student > Doctoral Student | 5 | 7% |
Researcher | 4 | 5% |
Other | 7 | 9% |
Unknown | 18 | 24% |
Readers by discipline | Count | As % |
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Neuroscience | 14 | 19% |
Biochemistry, Genetics and Molecular Biology | 12 | 16% |
Pharmacology, Toxicology and Pharmaceutical Science | 4 | 5% |
Medicine and Dentistry | 3 | 4% |
Other | 5 | 7% |
Unknown | 17 | 23% |