Sex and region-specific disruption of autophagy and mitophagy in Alzheimer’s disease: linking cellular dysfunction to cognitive decline
Abstract Macroautophagy and mitophagy are critical processes in Alzheimer’s disease (AD), yet their links to behavioral outcomes, particularly sex-specific differences, are not fully understood. This study investigates autophagic (LC3B-II, SQSTM1) and mitophagic (BNIP3L, BNIP3, BCL2L13) markers in t...
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| Format: | Article |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02490-0 |
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| author | Aida Adlimoghaddam Fariba Fayazbakhsh Mohsen Mohammadi Zeinab Babaei Amir Barzegar Behrooz Farhad Tabasi Teng Guan Iman Beheshti Mahmoud Aghaei Daniel J. Klionsky Benedict C. Albensi Saeid Ghavami |
| author_facet | Aida Adlimoghaddam Fariba Fayazbakhsh Mohsen Mohammadi Zeinab Babaei Amir Barzegar Behrooz Farhad Tabasi Teng Guan Iman Beheshti Mahmoud Aghaei Daniel J. Klionsky Benedict C. Albensi Saeid Ghavami |
| author_sort | Aida Adlimoghaddam |
| collection | DOAJ |
| description | Abstract Macroautophagy and mitophagy are critical processes in Alzheimer’s disease (AD), yet their links to behavioral outcomes, particularly sex-specific differences, are not fully understood. This study investigates autophagic (LC3B-II, SQSTM1) and mitophagic (BNIP3L, BNIP3, BCL2L13) markers in the cortex and hippocampus of male and female 3xTg-AD mice, using western blotting, transmission electron microscopy (TEM), and behavioral tests (novel object recognition and novel object placement). Significant sex-specific differences emerged: female 3xTg-AD mice exhibited autophagosome accumulation due to impaired degradation in the cortex, while males showed fewer autophagosomes, especially in the hippocampus, without significant degradation changes. TEM analyses demonstrated variations in mitochondrial and mitophagosome numbers correlated with memory outcomes. Females had enhanced mitophagy, with higher BNIP3L and BCL2L13 levels, whereas males showed elevated BNIP3 dimers. Cognitive deficits in females correlated with mitochondrial dysfunction in the cortex, while in males, higher LC3B-II levels associated positively with cognitive performance, suggesting protective autophagy effects. Using machine learning, we predicted mitophagosome and mitochondrial numbers based on behavioral data, pioneering a predictive approach to cellular outcomes in AD. These findings underscore the importance of sex-specific regulation of autophagy and mitophagy in AD and support personalized therapeutic approaches targeting these pathways. Integrating machine learning emphasizes its potential to advance neurodegenerative research. Sex-specific differences in autophagy and mitophagy regulation in Alzheimer’s disease (AD) are highlighted. Female 3xTg-AD mice show autophagosome accumulation and cognitive deficits, while males exhibit variations in mitophagy markers and behavior. |
| format | Article |
| id | doaj-art-c3d482bf49464d67ac1aec894c166ac1 |
| institution | OA Journals |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-c3d482bf49464d67ac1aec894c166ac12025-08-20T02:06:19ZengNature Publishing GroupCell Death Discovery2058-77162025-04-0111111310.1038/s41420-025-02490-0Sex and region-specific disruption of autophagy and mitophagy in Alzheimer’s disease: linking cellular dysfunction to cognitive declineAida Adlimoghaddam0Fariba Fayazbakhsh1Mohsen Mohammadi2Zeinab Babaei3Amir Barzegar Behrooz4Farhad Tabasi5Teng Guan6Iman Beheshti7Mahmoud Aghaei8Daniel J. Klionsky9Benedict C. Albensi10Saeid Ghavami11Department of Neurology, Dale and Deborah Smith Center for Alzheimer’s Research and Treatment, Neuroscience Institute, Southern Illinois University School of MedicineDepartment of Human Anatomy and Cell Science, University of ManitobaDepartment of Human Anatomy and Cell Science, University of ManitobaDepartment of Clinical Biochemistry and Biophysics, School of Medicine, Guilan University of Medical SciencesDepartment of Human Anatomy and Cell Science, University of ManitobaDepartment of Neurosurgery, University of Iowa Hospitals and ClinicsDepartment of Human Anatomy and Cell Science, University of ManitobaDepartment of Human Anatomy and Cell Science, University of ManitobaDepartment of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical SciencesDepartment of Molecular, Cellular and Developmental Biology and Life Sciences Institute, University of MichiganBarry and Judy Silverman College of Pharmacy, Nova Southeastern UniversityDepartment of Human Anatomy and Cell Science, University of ManitobaAbstract Macroautophagy and mitophagy are critical processes in Alzheimer’s disease (AD), yet their links to behavioral outcomes, particularly sex-specific differences, are not fully understood. This study investigates autophagic (LC3B-II, SQSTM1) and mitophagic (BNIP3L, BNIP3, BCL2L13) markers in the cortex and hippocampus of male and female 3xTg-AD mice, using western blotting, transmission electron microscopy (TEM), and behavioral tests (novel object recognition and novel object placement). Significant sex-specific differences emerged: female 3xTg-AD mice exhibited autophagosome accumulation due to impaired degradation in the cortex, while males showed fewer autophagosomes, especially in the hippocampus, without significant degradation changes. TEM analyses demonstrated variations in mitochondrial and mitophagosome numbers correlated with memory outcomes. Females had enhanced mitophagy, with higher BNIP3L and BCL2L13 levels, whereas males showed elevated BNIP3 dimers. Cognitive deficits in females correlated with mitochondrial dysfunction in the cortex, while in males, higher LC3B-II levels associated positively with cognitive performance, suggesting protective autophagy effects. Using machine learning, we predicted mitophagosome and mitochondrial numbers based on behavioral data, pioneering a predictive approach to cellular outcomes in AD. These findings underscore the importance of sex-specific regulation of autophagy and mitophagy in AD and support personalized therapeutic approaches targeting these pathways. Integrating machine learning emphasizes its potential to advance neurodegenerative research. Sex-specific differences in autophagy and mitophagy regulation in Alzheimer’s disease (AD) are highlighted. Female 3xTg-AD mice show autophagosome accumulation and cognitive deficits, while males exhibit variations in mitophagy markers and behavior.https://doi.org/10.1038/s41420-025-02490-0 |
| spellingShingle | Aida Adlimoghaddam Fariba Fayazbakhsh Mohsen Mohammadi Zeinab Babaei Amir Barzegar Behrooz Farhad Tabasi Teng Guan Iman Beheshti Mahmoud Aghaei Daniel J. Klionsky Benedict C. Albensi Saeid Ghavami Sex and region-specific disruption of autophagy and mitophagy in Alzheimer’s disease: linking cellular dysfunction to cognitive decline Cell Death Discovery |
| title | Sex and region-specific disruption of autophagy and mitophagy in Alzheimer’s disease: linking cellular dysfunction to cognitive decline |
| title_full | Sex and region-specific disruption of autophagy and mitophagy in Alzheimer’s disease: linking cellular dysfunction to cognitive decline |
| title_fullStr | Sex and region-specific disruption of autophagy and mitophagy in Alzheimer’s disease: linking cellular dysfunction to cognitive decline |
| title_full_unstemmed | Sex and region-specific disruption of autophagy and mitophagy in Alzheimer’s disease: linking cellular dysfunction to cognitive decline |
| title_short | Sex and region-specific disruption of autophagy and mitophagy in Alzheimer’s disease: linking cellular dysfunction to cognitive decline |
| title_sort | sex and region specific disruption of autophagy and mitophagy in alzheimer s disease linking cellular dysfunction to cognitive decline |
| url | https://doi.org/10.1038/s41420-025-02490-0 |
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