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Lactic Acid Induces Aberrant Amyloid Precursor Protein Processing by Promoting Its Interaction with Endoplasmic Reticulum Chaperone Proteins

BACKGROUND: Lactic acid, a natural by-product of glycolysis, is produced at excess levels in response to impaired mitochondrial function, high-energy demand, and low oxygen availability. The enzyme involved in the production of β-amyloid peptide (Aβ) of Alzheimer's disease, BACE1, functions opt...

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Autores principales: Xiang, Yiwen, Xu, Guilian, Weigel-Van Aken, Kirsten A. K.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2972223/
https://www.ncbi.nlm.nih.gov/pubmed/21072203
http://dx.doi.org/10.1371/journal.pone.0013820
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author Xiang, Yiwen
Xu, Guilian
Weigel-Van Aken, Kirsten A. K.
author_facet Xiang, Yiwen
Xu, Guilian
Weigel-Van Aken, Kirsten A. K.
author_sort Xiang, Yiwen
collection PubMed
description BACKGROUND: Lactic acid, a natural by-product of glycolysis, is produced at excess levels in response to impaired mitochondrial function, high-energy demand, and low oxygen availability. The enzyme involved in the production of β-amyloid peptide (Aβ) of Alzheimer's disease, BACE1, functions optimally at lower pH, which led us to investigate a potential role of lactic acid in the processing of amyloid precursor protein (APP). METHODOLOGY/PRINCIPAL FINDINGS: Lactic acid increased levels of Aβ40 and 42, as measured by ELISA, in culture medium of human neuroblastoma cells (SH-SY5Y), whereas it decreased APP metabolites, such as sAPPα. In cell lysates, APP levels were increased and APP was found to interact with ER-chaperones in a perinuclear region, as determined by co-immunoprecipitation and fluorescence microscopy studies. Lactic acid had only a very modest effect on cellular pH, did increase the levels of ER chaperones Grp78 and Grp94 and led to APP aggregate formation reminiscent of aggresomes. CONCLUSIONS/SIGNIFICANCE: These findings suggest that sustained elevations in lactic acid levels could be a risk factor in amyloidogenesis related to Alzheimer's disease through enhanced APP interaction with ER chaperone proteins and aberrant APP processing leading to increased generation of amyloid peptides and APP aggregates.
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spelling pubmed-29722232010-11-10 Lactic Acid Induces Aberrant Amyloid Precursor Protein Processing by Promoting Its Interaction with Endoplasmic Reticulum Chaperone Proteins Xiang, Yiwen Xu, Guilian Weigel-Van Aken, Kirsten A. K. PLoS One Research Article BACKGROUND: Lactic acid, a natural by-product of glycolysis, is produced at excess levels in response to impaired mitochondrial function, high-energy demand, and low oxygen availability. The enzyme involved in the production of β-amyloid peptide (Aβ) of Alzheimer's disease, BACE1, functions optimally at lower pH, which led us to investigate a potential role of lactic acid in the processing of amyloid precursor protein (APP). METHODOLOGY/PRINCIPAL FINDINGS: Lactic acid increased levels of Aβ40 and 42, as measured by ELISA, in culture medium of human neuroblastoma cells (SH-SY5Y), whereas it decreased APP metabolites, such as sAPPα. In cell lysates, APP levels were increased and APP was found to interact with ER-chaperones in a perinuclear region, as determined by co-immunoprecipitation and fluorescence microscopy studies. Lactic acid had only a very modest effect on cellular pH, did increase the levels of ER chaperones Grp78 and Grp94 and led to APP aggregate formation reminiscent of aggresomes. CONCLUSIONS/SIGNIFICANCE: These findings suggest that sustained elevations in lactic acid levels could be a risk factor in amyloidogenesis related to Alzheimer's disease through enhanced APP interaction with ER chaperone proteins and aberrant APP processing leading to increased generation of amyloid peptides and APP aggregates. Public Library of Science 2010-11-03 /pmc/articles/PMC2972223/ /pubmed/21072203 http://dx.doi.org/10.1371/journal.pone.0013820 Text en Xiang 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
Xiang, Yiwen
Xu, Guilian
Weigel-Van Aken, Kirsten A. K.
Lactic Acid Induces Aberrant Amyloid Precursor Protein Processing by Promoting Its Interaction with Endoplasmic Reticulum Chaperone Proteins
title Lactic Acid Induces Aberrant Amyloid Precursor Protein Processing by Promoting Its Interaction with Endoplasmic Reticulum Chaperone Proteins
title_full Lactic Acid Induces Aberrant Amyloid Precursor Protein Processing by Promoting Its Interaction with Endoplasmic Reticulum Chaperone Proteins
title_fullStr Lactic Acid Induces Aberrant Amyloid Precursor Protein Processing by Promoting Its Interaction with Endoplasmic Reticulum Chaperone Proteins
title_full_unstemmed Lactic Acid Induces Aberrant Amyloid Precursor Protein Processing by Promoting Its Interaction with Endoplasmic Reticulum Chaperone Proteins
title_short Lactic Acid Induces Aberrant Amyloid Precursor Protein Processing by Promoting Its Interaction with Endoplasmic Reticulum Chaperone Proteins
title_sort lactic acid induces aberrant amyloid precursor protein processing by promoting its interaction with endoplasmic reticulum chaperone proteins
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2972223/
https://www.ncbi.nlm.nih.gov/pubmed/21072203
http://dx.doi.org/10.1371/journal.pone.0013820
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