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Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease
This review is focused on the possible causes of mitochondrial dysfunction in AD, underlying molecular mechanisms of this malfunction, possible causes and known consequences of APP, Aβ, and hyperphosphorylated tau presence in mitochondria, and the contribution of altered lipid metabolism (nonsterol...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736771/ https://www.ncbi.nlm.nih.gov/pubmed/26881014 http://dx.doi.org/10.1155/2016/1805304 |
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author | Pająk, Beata Kania, Elżbieta Orzechowski, Arkadiusz |
author_facet | Pająk, Beata Kania, Elżbieta Orzechowski, Arkadiusz |
author_sort | Pająk, Beata |
collection | PubMed |
description | This review is focused on the possible causes of mitochondrial dysfunction in AD, underlying molecular mechanisms of this malfunction, possible causes and known consequences of APP, Aβ, and hyperphosphorylated tau presence in mitochondria, and the contribution of altered lipid metabolism (nonsterol isoprenoids) to pathological processes leading to increased formation and accumulation of the aforementioned hallmarks of AD. Abnormal protein folding and unfolded protein response seem to be the outcomes of impaired glycosylation due to metabolic disturbances in geranylgeraniol intermediary metabolism. The origin and consecutive fate of APP, Aβ, and tau are emphasized on intracellular trafficking apparently influenced by inaccurate posttranslational modifications. We hypothesize that incorrect intracellular processing of APP determines protein translocation to mitochondria in AD. Similarly, without obvious reasons, the passage of Aβ and tau to mitochondria is observed. APP targeted to mitochondria blocks the activity of protein translocase complex resulting in poor import of proteins central to oxidative phosphorylation. Besides, APP, Aβ, and neurofibrillary tangles of tau directly or indirectly impair mitochondrial biochemistry and bioenergetics, with concomitant generation of oxidative/nitrosative stress. Limited protective mechanisms are inadequate to prevent the free radical-mediated lesions. Finally, neuronal loss is observed in AD-affected brains typically by pathologic apoptosis. |
format | Online Article Text |
id | pubmed-4736771 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-47367712016-02-15 Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease Pająk, Beata Kania, Elżbieta Orzechowski, Arkadiusz Oxid Med Cell Longev Review Article This review is focused on the possible causes of mitochondrial dysfunction in AD, underlying molecular mechanisms of this malfunction, possible causes and known consequences of APP, Aβ, and hyperphosphorylated tau presence in mitochondria, and the contribution of altered lipid metabolism (nonsterol isoprenoids) to pathological processes leading to increased formation and accumulation of the aforementioned hallmarks of AD. Abnormal protein folding and unfolded protein response seem to be the outcomes of impaired glycosylation due to metabolic disturbances in geranylgeraniol intermediary metabolism. The origin and consecutive fate of APP, Aβ, and tau are emphasized on intracellular trafficking apparently influenced by inaccurate posttranslational modifications. We hypothesize that incorrect intracellular processing of APP determines protein translocation to mitochondria in AD. Similarly, without obvious reasons, the passage of Aβ and tau to mitochondria is observed. APP targeted to mitochondria blocks the activity of protein translocase complex resulting in poor import of proteins central to oxidative phosphorylation. Besides, APP, Aβ, and neurofibrillary tangles of tau directly or indirectly impair mitochondrial biochemistry and bioenergetics, with concomitant generation of oxidative/nitrosative stress. Limited protective mechanisms are inadequate to prevent the free radical-mediated lesions. Finally, neuronal loss is observed in AD-affected brains typically by pathologic apoptosis. Hindawi Publishing Corporation 2016 2016-01-06 /pmc/articles/PMC4736771/ /pubmed/26881014 http://dx.doi.org/10.1155/2016/1805304 Text en Copyright © 2016 Beata Pająk et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Review Article Pająk, Beata Kania, Elżbieta Orzechowski, Arkadiusz Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease |
title | Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease |
title_full | Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease |
title_fullStr | Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease |
title_full_unstemmed | Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease |
title_short | Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease |
title_sort | killing me softly: connotations to unfolded protein response and oxidative stress in alzheimer's disease |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736771/ https://www.ncbi.nlm.nih.gov/pubmed/26881014 http://dx.doi.org/10.1155/2016/1805304 |
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