Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer’s disease
Abstract Neurodegenerative diseases such as Alzheimer’s disease exhibit pathological changes in the brain that proceed in a stereotyped and regionally specific fashion. However, the cellular underpinnings of regional vulnerability are poorly understood, in part because whole-brain maps of a comprehe...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07575-1 |
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| author | Justin Torok Pedro D. Maia Chaitali Anand Ashish Raj |
| author_facet | Justin Torok Pedro D. Maia Chaitali Anand Ashish Raj |
| author_sort | Justin Torok |
| collection | DOAJ |
| description | Abstract Neurodegenerative diseases such as Alzheimer’s disease exhibit pathological changes in the brain that proceed in a stereotyped and regionally specific fashion. However, the cellular underpinnings of regional vulnerability are poorly understood, in part because whole-brain maps of a comprehensive collection of cell types have been inaccessible. Here, we deployed a recent cell-type mapping pipeline, Matrix Inversion and Subset Selection (MISS), to determine the brain-wide distributions of pan-hippocampal and neocortical cells in the mouse, and then used these maps to identify general principles of cell-type-based selective vulnerability in PS19 mouse models. We found that hippocampal glutamatergic neurons as a whole were significantly positively associated with regional tau deposition, suggesting vulnerability, while cortical glutamatergic and GABAergic neurons were negatively associated. We also identified oligodendrocytes as the single-most strongly negatively associated cell type. Further, cell-type distributions were more predictive of end-time-point tau pathology than AD-risk-gene expression. Using gene ontology analysis, we found that the genes that are directly correlated to tau pathology are functionally distinct from those that constitutively embody the vulnerable cells. In short, we have elucidated cell-type correlates of tau deposition across mouse models of tauopathy, advancing our understanding of selective cellular vulnerability at a whole-brain level. |
| format | Article |
| id | doaj-art-8e53591b465043619f7138a6d32b5c47 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-8e53591b465043619f7138a6d32b5c472025-02-09T12:50:30ZengNature PortfolioCommunications Biology2399-36422025-02-018111610.1038/s42003-025-07575-1Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer’s diseaseJustin Torok0Pedro D. Maia1Chaitali Anand2Ashish Raj3University of CAlifornia, San Francisco, Department of RadiologyUniversity of Texas at Arlington, Department of MathematicsUniversity of CAlifornia, San Francisco, Institute for Neurodegenerative DiseasesUniversity of CAlifornia, San Francisco, Department of RadiologyAbstract Neurodegenerative diseases such as Alzheimer’s disease exhibit pathological changes in the brain that proceed in a stereotyped and regionally specific fashion. However, the cellular underpinnings of regional vulnerability are poorly understood, in part because whole-brain maps of a comprehensive collection of cell types have been inaccessible. Here, we deployed a recent cell-type mapping pipeline, Matrix Inversion and Subset Selection (MISS), to determine the brain-wide distributions of pan-hippocampal and neocortical cells in the mouse, and then used these maps to identify general principles of cell-type-based selective vulnerability in PS19 mouse models. We found that hippocampal glutamatergic neurons as a whole were significantly positively associated with regional tau deposition, suggesting vulnerability, while cortical glutamatergic and GABAergic neurons were negatively associated. We also identified oligodendrocytes as the single-most strongly negatively associated cell type. Further, cell-type distributions were more predictive of end-time-point tau pathology than AD-risk-gene expression. Using gene ontology analysis, we found that the genes that are directly correlated to tau pathology are functionally distinct from those that constitutively embody the vulnerable cells. In short, we have elucidated cell-type correlates of tau deposition across mouse models of tauopathy, advancing our understanding of selective cellular vulnerability at a whole-brain level.https://doi.org/10.1038/s42003-025-07575-1 |
| spellingShingle | Justin Torok Pedro D. Maia Chaitali Anand Ashish Raj Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer’s disease Communications Biology |
| title | Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer’s disease |
| title_full | Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer’s disease |
| title_fullStr | Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer’s disease |
| title_full_unstemmed | Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer’s disease |
| title_short | Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer’s disease |
| title_sort | searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in alzheimer s disease |
| url | https://doi.org/10.1038/s42003-025-07575-1 |
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