Cargando…

Mild Oxidative Stress Induces Redistribution of BACE1 in Non-Apoptotic Conditions and Promotes the Amyloidogenic Processing of Alzheimer’s Disease Amyloid Precursor Protein

BACE1 is responsible for β-secretase cleavage of the amyloid precursor protein (APP), which represents the first step in the production of amyloid β (Aβ) peptides. Previous reports, by us and others, have indicated that the levels of BACE1 protein and activity are increased in the brain cortex of pa...

Descripción completa

Detalles Bibliográficos
Autores principales: Tan, Jiang-Li, Li, Qiao-Xin, Ciccotosto, Giuseppe D., Crouch, Peter John, Culvenor, Janetta Gladys, White, Anthony Robert, Evin, Genevieve
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629182/
https://www.ncbi.nlm.nih.gov/pubmed/23613819
http://dx.doi.org/10.1371/journal.pone.0061246
_version_ 1782266538138533888
author Tan, Jiang-Li
Li, Qiao-Xin
Ciccotosto, Giuseppe D.
Crouch, Peter John
Culvenor, Janetta Gladys
White, Anthony Robert
Evin, Genevieve
author_facet Tan, Jiang-Li
Li, Qiao-Xin
Ciccotosto, Giuseppe D.
Crouch, Peter John
Culvenor, Janetta Gladys
White, Anthony Robert
Evin, Genevieve
author_sort Tan, Jiang-Li
collection PubMed
description BACE1 is responsible for β-secretase cleavage of the amyloid precursor protein (APP), which represents the first step in the production of amyloid β (Aβ) peptides. Previous reports, by us and others, have indicated that the levels of BACE1 protein and activity are increased in the brain cortex of patients with Alzheimer’s disease (AD). The association between oxidative stress (OS) and AD has prompted investigations that support the potentiation of BACE1 expression and enzymatic activity by OS. Here, we have established conditions to analyse the effects of mild, non-lethal OS on BACE1 in primary neuronal cultures, independently from apoptotic mechanisms that were shown to impair BACE1 turnover. Six-hour treatment of mouse primary cortical cells with 10–40 µM hydrogen peroxide did not significantly compromise cell viability but it did produce mild oxidative stress (mOS), as shown by the increased levels of reactive radical species and activation of p38 stress kinase. The endogenous levels of BACE1 mRNA and protein were not significantly altered in these conditions, whereas a toxic H(2)O(2) concentration (100 µM) caused an increase in BACE1 protein levels. Notably, mOS conditions resulted in increased levels of the BACE1 C-terminal cleavage product of APP, β-CTF. Subcellular fractionation techniques showed that mOS caused a major rearrangement of BACE1 localization from light to denser fractions, resulting in an increased distribution of BACE1 in fractions containing APP and markers for trans-Golgi network and early endosomes. Collectively, these data demonstrate that mOS does not modify BACE1 expression but alters BACE1 subcellular compartmentalization to favour the amyloidogenic processing of APP, and thus offer new insight in the early molecular events of AD pathogenesis.
format Online
Article
Text
id pubmed-3629182
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-36291822013-04-23 Mild Oxidative Stress Induces Redistribution of BACE1 in Non-Apoptotic Conditions and Promotes the Amyloidogenic Processing of Alzheimer’s Disease Amyloid Precursor Protein Tan, Jiang-Li Li, Qiao-Xin Ciccotosto, Giuseppe D. Crouch, Peter John Culvenor, Janetta Gladys White, Anthony Robert Evin, Genevieve PLoS One Research Article BACE1 is responsible for β-secretase cleavage of the amyloid precursor protein (APP), which represents the first step in the production of amyloid β (Aβ) peptides. Previous reports, by us and others, have indicated that the levels of BACE1 protein and activity are increased in the brain cortex of patients with Alzheimer’s disease (AD). The association between oxidative stress (OS) and AD has prompted investigations that support the potentiation of BACE1 expression and enzymatic activity by OS. Here, we have established conditions to analyse the effects of mild, non-lethal OS on BACE1 in primary neuronal cultures, independently from apoptotic mechanisms that were shown to impair BACE1 turnover. Six-hour treatment of mouse primary cortical cells with 10–40 µM hydrogen peroxide did not significantly compromise cell viability but it did produce mild oxidative stress (mOS), as shown by the increased levels of reactive radical species and activation of p38 stress kinase. The endogenous levels of BACE1 mRNA and protein were not significantly altered in these conditions, whereas a toxic H(2)O(2) concentration (100 µM) caused an increase in BACE1 protein levels. Notably, mOS conditions resulted in increased levels of the BACE1 C-terminal cleavage product of APP, β-CTF. Subcellular fractionation techniques showed that mOS caused a major rearrangement of BACE1 localization from light to denser fractions, resulting in an increased distribution of BACE1 in fractions containing APP and markers for trans-Golgi network and early endosomes. Collectively, these data demonstrate that mOS does not modify BACE1 expression but alters BACE1 subcellular compartmentalization to favour the amyloidogenic processing of APP, and thus offer new insight in the early molecular events of AD pathogenesis. Public Library of Science 2013-04-17 /pmc/articles/PMC3629182/ /pubmed/23613819 http://dx.doi.org/10.1371/journal.pone.0061246 Text en © 2013 Tan et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tan, Jiang-Li
Li, Qiao-Xin
Ciccotosto, Giuseppe D.
Crouch, Peter John
Culvenor, Janetta Gladys
White, Anthony Robert
Evin, Genevieve
Mild Oxidative Stress Induces Redistribution of BACE1 in Non-Apoptotic Conditions and Promotes the Amyloidogenic Processing of Alzheimer’s Disease Amyloid Precursor Protein
title Mild Oxidative Stress Induces Redistribution of BACE1 in Non-Apoptotic Conditions and Promotes the Amyloidogenic Processing of Alzheimer’s Disease Amyloid Precursor Protein
title_full Mild Oxidative Stress Induces Redistribution of BACE1 in Non-Apoptotic Conditions and Promotes the Amyloidogenic Processing of Alzheimer’s Disease Amyloid Precursor Protein
title_fullStr Mild Oxidative Stress Induces Redistribution of BACE1 in Non-Apoptotic Conditions and Promotes the Amyloidogenic Processing of Alzheimer’s Disease Amyloid Precursor Protein
title_full_unstemmed Mild Oxidative Stress Induces Redistribution of BACE1 in Non-Apoptotic Conditions and Promotes the Amyloidogenic Processing of Alzheimer’s Disease Amyloid Precursor Protein
title_short Mild Oxidative Stress Induces Redistribution of BACE1 in Non-Apoptotic Conditions and Promotes the Amyloidogenic Processing of Alzheimer’s Disease Amyloid Precursor Protein
title_sort mild oxidative stress induces redistribution of bace1 in non-apoptotic conditions and promotes the amyloidogenic processing of alzheimer’s disease amyloid precursor protein
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629182/
https://www.ncbi.nlm.nih.gov/pubmed/23613819
http://dx.doi.org/10.1371/journal.pone.0061246
work_keys_str_mv AT tanjiangli mildoxidativestressinducesredistributionofbace1innonapoptoticconditionsandpromotestheamyloidogenicprocessingofalzheimersdiseaseamyloidprecursorprotein
AT liqiaoxin mildoxidativestressinducesredistributionofbace1innonapoptoticconditionsandpromotestheamyloidogenicprocessingofalzheimersdiseaseamyloidprecursorprotein
AT ciccotostogiusepped mildoxidativestressinducesredistributionofbace1innonapoptoticconditionsandpromotestheamyloidogenicprocessingofalzheimersdiseaseamyloidprecursorprotein
AT crouchpeterjohn mildoxidativestressinducesredistributionofbace1innonapoptoticconditionsandpromotestheamyloidogenicprocessingofalzheimersdiseaseamyloidprecursorprotein
AT culvenorjanettagladys mildoxidativestressinducesredistributionofbace1innonapoptoticconditionsandpromotestheamyloidogenicprocessingofalzheimersdiseaseamyloidprecursorprotein
AT whiteanthonyrobert mildoxidativestressinducesredistributionofbace1innonapoptoticconditionsandpromotestheamyloidogenicprocessingofalzheimersdiseaseamyloidprecursorprotein
AT evingenevieve mildoxidativestressinducesredistributionofbace1innonapoptoticconditionsandpromotestheamyloidogenicprocessingofalzheimersdiseaseamyloidprecursorprotein