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Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes

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 AP...

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Autores principales: Tang, Weihao, Tam, Joshua H.K., Seah, Claudia, Chiu, Justin, Tyrer, Andrea, Cregan, Sean P., Meakin, Susan O., Pasternak, Stephen H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501290/
https://www.ncbi.nlm.nih.gov/pubmed/26170135
http://dx.doi.org/10.1186/s13041-015-0129-7
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author Tang, Weihao
Tam, Joshua H.K.
Seah, Claudia
Chiu, Justin
Tyrer, Andrea
Cregan, Sean P.
Meakin, Susan O.
Pasternak, Stephen H.
author_facet Tang, Weihao
Tam, Joshua H.K.
Seah, Claudia
Chiu, Justin
Tyrer, Andrea
Cregan, Sean P.
Meakin, Susan O.
Pasternak, Stephen H.
author_sort Tang, Weihao
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-015-0129-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-45012902015-07-15 Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes Tang, Weihao Tam, Joshua H.K. Seah, Claudia Chiu, Justin Tyrer, Andrea Cregan, Sean P. Meakin, Susan O. Pasternak, Stephen H. Mol Brain Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-015-0129-7) contains supplementary material, which is available to authorized users. BioMed Central 2015-07-14 /pmc/articles/PMC4501290/ /pubmed/26170135 http://dx.doi.org/10.1186/s13041-015-0129-7 Text en © Tang et al. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Tang, Weihao
Tam, Joshua H.K.
Seah, Claudia
Chiu, Justin
Tyrer, Andrea
Cregan, Sean P.
Meakin, Susan O.
Pasternak, Stephen H.
Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes
title Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes
title_full Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes
title_fullStr Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes
title_full_unstemmed Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes
title_short Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes
title_sort arf6 controls beta-amyloid production by regulating macropinocytosis of the amyloid precursor protein to lysosomes
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501290/
https://www.ncbi.nlm.nih.gov/pubmed/26170135
http://dx.doi.org/10.1186/s13041-015-0129-7
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