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.