Cargando…
The unfolded protein response is activated in the olfactory system in Alzheimer’s disease
Olfactory dysfunction is an early and prevalent symptom of Alzheimer’s disease (AD) and the olfactory bulb is a nexus of beta-amyloid plaque and tau neurofibrillary tangle (NFT) pathology during early AD progression. To mitigate the accumulation of misfolded proteins, an endoplasmic reticulum stress...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362534/ https://www.ncbi.nlm.nih.gov/pubmed/32665027 http://dx.doi.org/10.1186/s40478-020-00986-7 |
_version_ | 1783559510965616640 |
---|---|
author | Murray, Helen C. Dieriks, Birger Victor Swanson, Molly E. V. Anekal, Praju Vikas Turner, Clinton Faull, Richard L. M. Belluscio, Leonardo Koretsky, Alan Curtis, Maurice A. |
author_facet | Murray, Helen C. Dieriks, Birger Victor Swanson, Molly E. V. Anekal, Praju Vikas Turner, Clinton Faull, Richard L. M. Belluscio, Leonardo Koretsky, Alan Curtis, Maurice A. |
author_sort | Murray, Helen C. |
collection | PubMed |
description | Olfactory dysfunction is an early and prevalent symptom of Alzheimer’s disease (AD) and the olfactory bulb is a nexus of beta-amyloid plaque and tau neurofibrillary tangle (NFT) pathology during early AD progression. To mitigate the accumulation of misfolded proteins, an endoplasmic reticulum stress response called the unfolded protein response (UPR) occurs in the AD hippocampus. However, chronic UPR activation can lead to apoptosis and the upregulation of beta-amyloid and tau production. Therefore, UPR activation in the olfactory system could be one of the first changes in AD. In this study, we investigated whether two proteins that signal UPR activation are expressed in the olfactory system of AD cases with low or high amounts of aggregate pathology. We used immunohistochemistry to label two markers of UPR activation (p-PERK and p-eIF2α) concomitantly with neuronal markers (NeuN and PGP9.5) and pathology markers (beta-amyloid and tau) in the olfactory bulb, piriform cortex, entorhinal cortex and the CA1 region of the hippocampus in AD and normal cases. We show that UPR activation, as indicated by p-PERK and p-eIF2α expression, is significantly increased throughout the olfactory system in AD cases with low (Braak stage III-IV) and high-level (Braak stage V-VI) pathology. We further show that UPR activation occurs in the mitral cells and in the anterior olfactory nucleus of the olfactory bulb where tau and amyloid pathology is abundant. However, UPR activation is not present in neurons when they contain NFTs and only rarely occurs in neurons containing diffuse tau aggregates. We conclude that UPR activation is prevalent in all regions of the olfactory system and support previous findings suggesting that UPR activation likely precedes NFT formation. Our data indicate that chronic UPR activation in the olfactory system might contribute to the olfactory dysfunction that occurs early in the pathogenesis of AD. |
format | Online Article Text |
id | pubmed-7362534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-73625342020-07-17 The unfolded protein response is activated in the olfactory system in Alzheimer’s disease Murray, Helen C. Dieriks, Birger Victor Swanson, Molly E. V. Anekal, Praju Vikas Turner, Clinton Faull, Richard L. M. Belluscio, Leonardo Koretsky, Alan Curtis, Maurice A. Acta Neuropathol Commun Research Olfactory dysfunction is an early and prevalent symptom of Alzheimer’s disease (AD) and the olfactory bulb is a nexus of beta-amyloid plaque and tau neurofibrillary tangle (NFT) pathology during early AD progression. To mitigate the accumulation of misfolded proteins, an endoplasmic reticulum stress response called the unfolded protein response (UPR) occurs in the AD hippocampus. However, chronic UPR activation can lead to apoptosis and the upregulation of beta-amyloid and tau production. Therefore, UPR activation in the olfactory system could be one of the first changes in AD. In this study, we investigated whether two proteins that signal UPR activation are expressed in the olfactory system of AD cases with low or high amounts of aggregate pathology. We used immunohistochemistry to label two markers of UPR activation (p-PERK and p-eIF2α) concomitantly with neuronal markers (NeuN and PGP9.5) and pathology markers (beta-amyloid and tau) in the olfactory bulb, piriform cortex, entorhinal cortex and the CA1 region of the hippocampus in AD and normal cases. We show that UPR activation, as indicated by p-PERK and p-eIF2α expression, is significantly increased throughout the olfactory system in AD cases with low (Braak stage III-IV) and high-level (Braak stage V-VI) pathology. We further show that UPR activation occurs in the mitral cells and in the anterior olfactory nucleus of the olfactory bulb where tau and amyloid pathology is abundant. However, UPR activation is not present in neurons when they contain NFTs and only rarely occurs in neurons containing diffuse tau aggregates. We conclude that UPR activation is prevalent in all regions of the olfactory system and support previous findings suggesting that UPR activation likely precedes NFT formation. Our data indicate that chronic UPR activation in the olfactory system might contribute to the olfactory dysfunction that occurs early in the pathogenesis of AD. BioMed Central 2020-07-14 /pmc/articles/PMC7362534/ /pubmed/32665027 http://dx.doi.org/10.1186/s40478-020-00986-7 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data. |
spellingShingle | Research Murray, Helen C. Dieriks, Birger Victor Swanson, Molly E. V. Anekal, Praju Vikas Turner, Clinton Faull, Richard L. M. Belluscio, Leonardo Koretsky, Alan Curtis, Maurice A. The unfolded protein response is activated in the olfactory system in Alzheimer’s disease |
title | The unfolded protein response is activated in the olfactory system in Alzheimer’s disease |
title_full | The unfolded protein response is activated in the olfactory system in Alzheimer’s disease |
title_fullStr | The unfolded protein response is activated in the olfactory system in Alzheimer’s disease |
title_full_unstemmed | The unfolded protein response is activated in the olfactory system in Alzheimer’s disease |
title_short | The unfolded protein response is activated in the olfactory system in Alzheimer’s disease |
title_sort | unfolded protein response is activated in the olfactory system in alzheimer’s disease |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362534/ https://www.ncbi.nlm.nih.gov/pubmed/32665027 http://dx.doi.org/10.1186/s40478-020-00986-7 |
work_keys_str_mv | AT murrayhelenc theunfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT dieriksbirgervictor theunfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT swansonmollyev theunfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT anekalprajuvikas theunfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT turnerclinton theunfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT faullrichardlm theunfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT belluscioleonardo theunfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT koretskyalan theunfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT curtismauricea theunfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT murrayhelenc unfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT dieriksbirgervictor unfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT swansonmollyev unfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT anekalprajuvikas unfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT turnerclinton unfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT faullrichardlm unfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT belluscioleonardo unfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT koretskyalan unfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease AT curtismauricea unfoldedproteinresponseisactivatedintheolfactorysysteminalzheimersdisease |