The Unfolded Protein Response in a Murine Model of Alzheimer’s Disease: Looking for Predictors
Alzheimer’s disease (AD) represents the most frequent type of dementia worldwide, and aging is the most important risk factor for the sporadic form of the pathology. The endoplasmic reticulum (ER), the main cellular actor involved in proteostasis, appears significantly compromised in AD due to the a...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/22/16200 |
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| author | Giulia Sita Agnese Graziosi Camilla Corrieri Luca Ghelli Sabrina Angelini Pietro Cortelli Patrizia Hrelia Fabiana Morroni |
| author_facet | Giulia Sita Agnese Graziosi Camilla Corrieri Luca Ghelli Sabrina Angelini Pietro Cortelli Patrizia Hrelia Fabiana Morroni |
| author_sort | Giulia Sita |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) represents the most frequent type of dementia worldwide, and aging is the most important risk factor for the sporadic form of the pathology. The endoplasmic reticulum (ER), the main cellular actor involved in proteostasis, appears significantly compromised in AD due to the accumulation of the β-amyloid (Aβ) protein and the phosphorylated Tau protein. Increasing protein misfolding activates a specific cellular response known as Unfolded Protein Response (UPR), which orchestrates the recovery of ER function. The aim of the present study was to investigate the role of UPR in a murine model of AD induced by intracerebroventricular (i.c.v.) injection of Aβ<sub>1–42</sub> oligomers at 3 or 18 months. The oligomer injection in aged animals induced memory impairment, oxidative stress, and the depletion of glutathione reserve. Furthermore, the RNA sequencing and the bioinformatic analysis performed showed the enrichment of several pathways involved in neurodegeneration and protein regulations. The analysis highlighted the significant dysregulation of the protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF-6). In turn, ER stress affected the PI3K/Akt/Gsk3β and MAPK/ERK pathways, highlighting Mapkapk5 as a potential marker, whose regulation could lead to the definition of new pharmacological and neuroprotective strategies to counteract AD. |
| first_indexed | 2024-03-09T16:45:45Z |
| format | Article |
| id | doaj.art-393e4f7880b64d6eb52a94ee955907aa |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T16:45:45Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-393e4f7880b64d6eb52a94ee955907aa2023-11-24T14:46:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124221620010.3390/ijms242216200The Unfolded Protein Response in a Murine Model of Alzheimer’s Disease: Looking for PredictorsGiulia Sita0Agnese Graziosi1Camilla Corrieri2Luca Ghelli3Sabrina Angelini4Pietro Cortelli5Patrizia Hrelia6Fabiana Morroni7Department of Pharmacy and BioTechnology—FaBiT, Alma Mater Studiorum University of Bologna, Via Irnerio 48, 40126 Bologna, ItalyDepartment of Pharmacy and BioTechnology—FaBiT, Alma Mater Studiorum University of Bologna, Via Irnerio 48, 40126 Bologna, ItalyDepartment of Pharmacy and BioTechnology—FaBiT, Alma Mater Studiorum University of Bologna, Via Irnerio 48, 40126 Bologna, ItalyDepartment of Pharmacy and BioTechnology—FaBiT, Alma Mater Studiorum University of Bologna, Via Irnerio 48, 40126 Bologna, ItalyDepartment of Pharmacy and BioTechnology—FaBiT, Alma Mater Studiorum University of Bologna, Via Irnerio 48, 40126 Bologna, ItalyDepartment of Biomedical and NeuroMotor Sciences—DiBiNeM, Alma Mater Studiorum University of Bologna, Via Altura 3, 40139 Bologna, ItalyDepartment of Pharmacy and BioTechnology—FaBiT, Alma Mater Studiorum University of Bologna, Via Irnerio 48, 40126 Bologna, ItalyDepartment of Pharmacy and BioTechnology—FaBiT, Alma Mater Studiorum University of Bologna, Via Irnerio 48, 40126 Bologna, ItalyAlzheimer’s disease (AD) represents the most frequent type of dementia worldwide, and aging is the most important risk factor for the sporadic form of the pathology. The endoplasmic reticulum (ER), the main cellular actor involved in proteostasis, appears significantly compromised in AD due to the accumulation of the β-amyloid (Aβ) protein and the phosphorylated Tau protein. Increasing protein misfolding activates a specific cellular response known as Unfolded Protein Response (UPR), which orchestrates the recovery of ER function. The aim of the present study was to investigate the role of UPR in a murine model of AD induced by intracerebroventricular (i.c.v.) injection of Aβ<sub>1–42</sub> oligomers at 3 or 18 months. The oligomer injection in aged animals induced memory impairment, oxidative stress, and the depletion of glutathione reserve. Furthermore, the RNA sequencing and the bioinformatic analysis performed showed the enrichment of several pathways involved in neurodegeneration and protein regulations. The analysis highlighted the significant dysregulation of the protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF-6). In turn, ER stress affected the PI3K/Akt/Gsk3β and MAPK/ERK pathways, highlighting Mapkapk5 as a potential marker, whose regulation could lead to the definition of new pharmacological and neuroprotective strategies to counteract AD.https://www.mdpi.com/1422-0067/24/22/16200Aβ oligomersagingAlzheimer’s diseaseneurodegenerationUPR |
| spellingShingle | Giulia Sita Agnese Graziosi Camilla Corrieri Luca Ghelli Sabrina Angelini Pietro Cortelli Patrizia Hrelia Fabiana Morroni The Unfolded Protein Response in a Murine Model of Alzheimer’s Disease: Looking for Predictors International Journal of Molecular Sciences Aβ oligomers aging Alzheimer’s disease neurodegeneration UPR |
| title | The Unfolded Protein Response in a Murine Model of Alzheimer’s Disease: Looking for Predictors |
| title_full | The Unfolded Protein Response in a Murine Model of Alzheimer’s Disease: Looking for Predictors |
| title_fullStr | The Unfolded Protein Response in a Murine Model of Alzheimer’s Disease: Looking for Predictors |
| title_full_unstemmed | The Unfolded Protein Response in a Murine Model of Alzheimer’s Disease: Looking for Predictors |
| title_short | The Unfolded Protein Response in a Murine Model of Alzheimer’s Disease: Looking for Predictors |
| title_sort | unfolded protein response in a murine model of alzheimer s disease looking for predictors |
| topic | Aβ oligomers aging Alzheimer’s disease neurodegeneration UPR |
| url | https://www.mdpi.com/1422-0067/24/22/16200 |
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