Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology
Abstract Aging is the main risk factor for Alzheimer’s disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes underlying pathological aging of the nervous system are poorly understood. AD pathology seems to correlate with the appearance of cells that become sene...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01578-x |
| _version_ | 1797822601264889856 |
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| author | Nuria Suelves Shirine Saleki Tasha Ibrahim Debora Palomares Sebastiaan Moonen Marta J. Koper Céline Vrancx Devkee M. Vadukul Nicolas Papadopoulos Nikenza Viceconte Eloïse Claude Rik Vandenberghe Christine A. F. von Arnim Stefan N. Constantinescu Dietmar Rudolf Thal Anabelle Decottignies Pascal Kienlen-Campard |
| author_facet | Nuria Suelves Shirine Saleki Tasha Ibrahim Debora Palomares Sebastiaan Moonen Marta J. Koper Céline Vrancx Devkee M. Vadukul Nicolas Papadopoulos Nikenza Viceconte Eloïse Claude Rik Vandenberghe Christine A. F. von Arnim Stefan N. Constantinescu Dietmar Rudolf Thal Anabelle Decottignies Pascal Kienlen-Campard |
| author_sort | Nuria Suelves |
| collection | DOAJ |
| description | Abstract Aging is the main risk factor for Alzheimer’s disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes underlying pathological aging of the nervous system are poorly understood. AD pathology seems to correlate with the appearance of cells that become senescent due to the progressive accumulation of cellular insults causing DNA damage. Senescence has also been shown to reduce the autophagic flux, a mechanism involved in clearing damaged proteins from the cell, and such impairment has been linked to AD pathogenesis. In this study, we investigated the role of cellular senescence on AD pathology by crossing a mouse model of AD-like amyloid-β (Aβ) pathology (5xFAD) with a mouse model of senescence that is genetically deficient for the RNA component of the telomerase (Terc−/−). We studied changes in amyloid pathology, neurodegeneration, and the autophagy process in brain tissue samples and primary cultures derived from these mice by complementary biochemical and immunostaining approaches. Postmortem human brain samples were also processed to evaluate autophagy defects in AD patients. Our results show that accelerated senescence produces an early accumulation of intraneuronal Aβ in the subiculum and cortical layer V of 5xFAD mice. This correlates with a reduction in amyloid plaques and Aβ levels in connecting brain regions at a later disease stage. Neuronal loss was specifically observed in brain regions presenting intraneuronal Aβ and was linked to telomere attrition. Our results indicate that senescence affects intraneuronal Aβ accumulation by impairing autophagy function and that early autophagy defects can be found in the brains of AD patients. Together, these findings demonstrate the instrumental role of senescence in intraneuronal Aβ accumulation, which represents a key event in AD pathophysiology, and emphasize the correlation between the initial stages of amyloid pathology and defects in the autophagy flux. |
| first_indexed | 2024-03-13T10:11:30Z |
| format | Article |
| id | doaj.art-5f4fdaf58fee4378a6e15e3c44d2238d |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-13T10:11:30Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-5f4fdaf58fee4378a6e15e3c44d2238d2023-05-21T11:29:51ZengBMCActa Neuropathologica Communications2051-59602023-05-0111112610.1186/s40478-023-01578-xSenescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathologyNuria Suelves0Shirine Saleki1Tasha Ibrahim2Debora Palomares3Sebastiaan Moonen4Marta J. Koper5Céline Vrancx6Devkee M. Vadukul7Nicolas Papadopoulos8Nikenza Viceconte9Eloïse Claude10Rik Vandenberghe11Christine A. F. von Arnim12Stefan N. Constantinescu13Dietmar Rudolf Thal14Anabelle Decottignies15Pascal Kienlen-Campard16Aging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvainAging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvainAging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvainAging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvainLaboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU LeuvenLaboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU LeuvenAging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvainAging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvainLudwig Institute for Cancer ResearchGenetic and Epigenetic Alterations of Genomes Unit, de Duve Institute, UCLouvainGenetic and Epigenetic Alterations of Genomes Unit, de Duve Institute, UCLouvainLaboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven)Department of Neurology, University of UlmLudwig Institute for Cancer ResearchLaboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU LeuvenGenetic and Epigenetic Alterations of Genomes Unit, de Duve Institute, UCLouvainAging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvainAbstract Aging is the main risk factor for Alzheimer’s disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes underlying pathological aging of the nervous system are poorly understood. AD pathology seems to correlate with the appearance of cells that become senescent due to the progressive accumulation of cellular insults causing DNA damage. Senescence has also been shown to reduce the autophagic flux, a mechanism involved in clearing damaged proteins from the cell, and such impairment has been linked to AD pathogenesis. In this study, we investigated the role of cellular senescence on AD pathology by crossing a mouse model of AD-like amyloid-β (Aβ) pathology (5xFAD) with a mouse model of senescence that is genetically deficient for the RNA component of the telomerase (Terc−/−). We studied changes in amyloid pathology, neurodegeneration, and the autophagy process in brain tissue samples and primary cultures derived from these mice by complementary biochemical and immunostaining approaches. Postmortem human brain samples were also processed to evaluate autophagy defects in AD patients. Our results show that accelerated senescence produces an early accumulation of intraneuronal Aβ in the subiculum and cortical layer V of 5xFAD mice. This correlates with a reduction in amyloid plaques and Aβ levels in connecting brain regions at a later disease stage. Neuronal loss was specifically observed in brain regions presenting intraneuronal Aβ and was linked to telomere attrition. Our results indicate that senescence affects intraneuronal Aβ accumulation by impairing autophagy function and that early autophagy defects can be found in the brains of AD patients. Together, these findings demonstrate the instrumental role of senescence in intraneuronal Aβ accumulation, which represents a key event in AD pathophysiology, and emphasize the correlation between the initial stages of amyloid pathology and defects in the autophagy flux.https://doi.org/10.1186/s40478-023-01578-xCellular senescenceTelomere shorteningAlzheimer’s diseaseIntraneuronal AβAutophagy |
| spellingShingle | Nuria Suelves Shirine Saleki Tasha Ibrahim Debora Palomares Sebastiaan Moonen Marta J. Koper Céline Vrancx Devkee M. Vadukul Nicolas Papadopoulos Nikenza Viceconte Eloïse Claude Rik Vandenberghe Christine A. F. von Arnim Stefan N. Constantinescu Dietmar Rudolf Thal Anabelle Decottignies Pascal Kienlen-Campard Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology Acta Neuropathologica Communications Cellular senescence Telomere shortening Alzheimer’s disease Intraneuronal Aβ Autophagy |
| title | Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology |
| title_full | Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology |
| title_fullStr | Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology |
| title_full_unstemmed | Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology |
| title_short | Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology |
| title_sort | senescence related impairment of autophagy induces toxic intraneuronal amyloid β accumulation in a mouse model of amyloid pathology |
| topic | Cellular senescence Telomere shortening Alzheimer’s disease Intraneuronal Aβ Autophagy |
| url | https://doi.org/10.1186/s40478-023-01578-x |
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