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. Furt..., Gene expression
The scRNAseq data used to generate the cell-type maps come from Yao, et al. for the Allen Institute for Brain Science (AIBS), which sequenced approximately 1.3 million individual cells sampled comprehensively throughout the neocortex and hippocampal formation at 10x sequencing depth (Yao et al, 2021, Cell). Using a standard Jaccard-Louvain clustering algorithm, the authors jointly and hierarchically clustered these samples at three taxonomic levels: class (n = 4), subclass (n = 42), and cluster (n = 387). The full annotation and gene expression profile of each sample, as well as trimmed mean expression across cell-type clusters, are publicly available (https://portal.brain-map.org/atlases-and-data/rnaseq/mouse-whole-cortex-and-hippocampus-10x). Here we used this trimmed means by cluster dataset, as the Matrix Inversion and Subset Selection (MISS) algorithm only requires the consensus profiles of cell types per cluster. Utilizing the hierarchical taxonomy provided by the ..., , # Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer's disease

[https://doi.org/10.5061/dryad.h18931zwv](https://doi.org/10.5061/dryad.h18931zwv)

## Description of the data and file structure

### Files and variables

#### File: Yao\_Dependencies.mat

**Description:** Contains all cell density and gene expression files required to run the analyses in the paper.

##### Variables

* classkey: 42 x 1 cell array of Yao cell-type names
* gene_names: 3763 x 1 cell array of gene symbols for the intersection set of genes between the scRNAseq (Yao et al, 2021, *Cell*) and ISH (Lein et al, 2007, *Nature*) datasets
* geneinds: 1 x 3763 numeric array of MRx3-reordered gene indices in \"gene_names\" (see Mezias et al, 2022, *PNAS* and [https://github.com/Raj-Lab-UCSF/MISS-Pipeline](https://github.com/Raj-Lab-UCSF/MISS-Pipeline))
* genevct: 3763 x 42 numeric array of cell-type-specific gene expression across all 42 Yao cell types and 3763 inters...