Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer’s disease

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.