The unfolded protein response is activated in the olfactory system in Alzheimer’s disease
Abstract 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 reticul...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-07-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-020-00986-7 |
| _version_ | 1818097286370033664 |
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| author | Helen C. Murray Birger Victor Dieriks Molly E. V. Swanson Praju Vikas Anekal Clinton Turner Richard L. M. Faull Leonardo Belluscio Alan Koretsky Maurice A. Curtis |
| author_facet | Helen C. Murray Birger Victor Dieriks Molly E. V. Swanson Praju Vikas Anekal Clinton Turner Richard L. M. Faull Leonardo Belluscio Alan Koretsky Maurice A. Curtis |
| author_sort | Helen C. Murray |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-10T23:18:06Z |
| format | Article |
| id | doaj.art-e03ed8358b8a4a90b1985b46dadf7659 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-10T23:18:06Z |
| publishDate | 2020-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-e03ed8358b8a4a90b1985b46dadf76592022-12-22T01:29:48ZengBMCActa Neuropathologica Communications2051-59602020-07-018111510.1186/s40478-020-00986-7The unfolded protein response is activated in the olfactory system in Alzheimer’s diseaseHelen C. Murray0Birger Victor Dieriks1Molly E. V. Swanson2Praju Vikas Anekal3Clinton Turner4Richard L. M. Faull5Leonardo Belluscio6Alan Koretsky7Maurice A. Curtis8Department of Anatomy and Medical Imaging and Centre for Brain Research, Faculty of Medical and Health Science, University of AucklandDepartment of Anatomy and Medical Imaging and Centre for Brain Research, Faculty of Medical and Health Science, University of AucklandDepartment of Anatomy and Medical Imaging and Centre for Brain Research, Faculty of Medical and Health Science, University of AucklandDepartment of Anatomy and Medical Imaging and Centre for Brain Research, Faculty of Medical and Health Science, University of AucklandDepartment of Anatomical Pathology, LabPlus, Auckland City HospitalDepartment of Anatomy and Medical Imaging and Centre for Brain Research, Faculty of Medical and Health Science, University of AucklandHoward Hughes Medical InstituteLaboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of HealthDepartment of Anatomy and Medical Imaging and Centre for Brain Research, Faculty of Medical and Health Science, University of AucklandAbstract 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.http://link.springer.com/article/10.1186/s40478-020-00986-7Alzheimer’s diseaseUnfolded protein responseOlfactory bulbAnterior olfactory nucleusPERKeIF2α |
| spellingShingle | Helen C. Murray Birger Victor Dieriks Molly E. V. Swanson Praju Vikas Anekal Clinton Turner Richard L. M. Faull Leonardo Belluscio Alan Koretsky Maurice A. Curtis The unfolded protein response is activated in the olfactory system in Alzheimer’s disease Acta Neuropathologica Communications Alzheimer’s disease Unfolded protein response Olfactory bulb Anterior olfactory nucleus PERK eIF2α |
| 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 | Alzheimer’s disease Unfolded protein response Olfactory bulb Anterior olfactory nucleus PERK eIF2α |
| url | http://link.springer.com/article/10.1186/s40478-020-00986-7 |
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