HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer’s disease
Abstract Many studies highlight the potential link between the chronic degenerative Alzheimer’s disease and the infection by the herpes simplex virus type-1 (HSV-1). However, the molecular mechanisms making possible this HSV-1-dependent process remain to be understood. Using neuronal cells expressin...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-03-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-023-02376-8 |
| _version_ | 1797863443632488448 |
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| author | Marie Alexandra Albaret Julien Textoris Bastien Dalzon Jérémy Lambert Morgane Linard Catherine Helmer Sabine Hacot Sandra E. Ghayad Martial Ferréol Hichem C. Mertani Jean-Jacques Diaz |
| author_facet | Marie Alexandra Albaret Julien Textoris Bastien Dalzon Jérémy Lambert Morgane Linard Catherine Helmer Sabine Hacot Sandra E. Ghayad Martial Ferréol Hichem C. Mertani Jean-Jacques Diaz |
| author_sort | Marie Alexandra Albaret |
| collection | DOAJ |
| description | Abstract Many studies highlight the potential link between the chronic degenerative Alzheimer’s disease and the infection by the herpes simplex virus type-1 (HSV-1). However, the molecular mechanisms making possible this HSV-1-dependent process remain to be understood. Using neuronal cells expressing the wild type form of amyloid precursor protein (APP) infected by HSV-1, we characterized a representative cellular model of the early stage of the sporadic form of the disease and unraveled a molecular mechanism sustaining this HSV-1- Alzheimer’s disease interplay. Here, we show that HSV-1 induces caspase-dependent production of the 42 amino-acid long amyloid peptide (Aβ42) oligomers followed by their accumulation in neuronal cells. Aβ42 oligomers and activated caspase 3 (casp3A) concentrate into intracytoplasmic structures observed in Alzheimer’s disease neuronal cells called aggresomes. This casp3A accumulation in aggresomes during HSV-1 infection limits the execution of apoptosis until its term, similarly to an abortosis-like event occurring in Alzheimer’s disease neuronal cells patients. Indeed, this particular HSV-1 driven cellular context, representative of early stages of the disease, sustains a failed apoptosis mechanism that could explain the chronic amplification of Aβ42 production characteristic of Alzheimer’s disease patients. Finally, we show that combination of flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), with caspase inhibitor reduced drastically HSV-1-induced Aβ42 oligomers production. This provided mechanistic insights supporting the conclusion of clinical trials showing that NSAIDs reduced Alzheimer’s disease incidence in early stage of the disease. Therefore, from our study we propose that caspase-dependent production of Aβ42 oligomers together with the abortosis-like event represents a vicious circle in early Alzheimer’s disease stages leading to a chronic amplification of Aβ42 oligomers that contributes to the establishment of degenerative disorder like Alzheimer’s disease in patients infected by HSV-1. Interestingly this process could be targeted by an association of NSAID with caspase inhibitors. |
| first_indexed | 2024-04-09T22:35:41Z |
| format | Article |
| id | doaj.art-1039b9bf4bfc4c8cb63a68facbaa9294 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-04-09T22:35:41Z |
| publishDate | 2023-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-1039b9bf4bfc4c8cb63a68facbaa92942023-03-22T12:27:05ZengNature Publishing GroupTranslational Psychiatry2158-31882023-03-0113111210.1038/s41398-023-02376-8HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer’s diseaseMarie Alexandra Albaret0Julien Textoris1Bastien Dalzon2Jérémy Lambert3Morgane Linard4Catherine Helmer5Sabine Hacot6Sandra E. Ghayad7Martial Ferréol8Hichem C. Mertani9Jean-Jacques Diaz10Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonEA7426, Joint Research Unit, bioMerieux-HCL-UCBL1, hôpital Edouard Herriot 5 place d’ArsonvalChemistry and Biology of Metals, Univ. Grenoble Alpes, CNRS UMR5249, CEA, IRIG, CBM- ProMIT, 17 Avenue des MartyrsUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonUniversity of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR U1219University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR U1219Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonCenter for CardioVascular and Nutrition Research (C2VN), INSERM 1263, INRAE 1260, Aix-Marseille University, Faculty of PharmacyINRAE, Ecoflows, UR RiverLy, BP 32108, 69616, 5 Rue de la DouaUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonAbstract Many studies highlight the potential link between the chronic degenerative Alzheimer’s disease and the infection by the herpes simplex virus type-1 (HSV-1). However, the molecular mechanisms making possible this HSV-1-dependent process remain to be understood. Using neuronal cells expressing the wild type form of amyloid precursor protein (APP) infected by HSV-1, we characterized a representative cellular model of the early stage of the sporadic form of the disease and unraveled a molecular mechanism sustaining this HSV-1- Alzheimer’s disease interplay. Here, we show that HSV-1 induces caspase-dependent production of the 42 amino-acid long amyloid peptide (Aβ42) oligomers followed by their accumulation in neuronal cells. Aβ42 oligomers and activated caspase 3 (casp3A) concentrate into intracytoplasmic structures observed in Alzheimer’s disease neuronal cells called aggresomes. This casp3A accumulation in aggresomes during HSV-1 infection limits the execution of apoptosis until its term, similarly to an abortosis-like event occurring in Alzheimer’s disease neuronal cells patients. Indeed, this particular HSV-1 driven cellular context, representative of early stages of the disease, sustains a failed apoptosis mechanism that could explain the chronic amplification of Aβ42 production characteristic of Alzheimer’s disease patients. Finally, we show that combination of flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), with caspase inhibitor reduced drastically HSV-1-induced Aβ42 oligomers production. This provided mechanistic insights supporting the conclusion of clinical trials showing that NSAIDs reduced Alzheimer’s disease incidence in early stage of the disease. Therefore, from our study we propose that caspase-dependent production of Aβ42 oligomers together with the abortosis-like event represents a vicious circle in early Alzheimer’s disease stages leading to a chronic amplification of Aβ42 oligomers that contributes to the establishment of degenerative disorder like Alzheimer’s disease in patients infected by HSV-1. Interestingly this process could be targeted by an association of NSAID with caspase inhibitors.https://doi.org/10.1038/s41398-023-02376-8 |
| spellingShingle | Marie Alexandra Albaret Julien Textoris Bastien Dalzon Jérémy Lambert Morgane Linard Catherine Helmer Sabine Hacot Sandra E. Ghayad Martial Ferréol Hichem C. Mertani Jean-Jacques Diaz HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer’s disease Translational Psychiatry |
| title | HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer’s disease |
| title_full | HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer’s disease |
| title_fullStr | HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer’s disease |
| title_full_unstemmed | HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer’s disease |
| title_short | HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer’s disease |
| title_sort | hsv 1 cellular model reveals links between aggresome formation and early step of alzheimer s disease |
| url | https://doi.org/10.1038/s41398-023-02376-8 |
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