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Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
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Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
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Journal Article
Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
2023
Overview
Genetic studies of Alzheimer disease (AD) have prioritized variants in genes related to the amyloid cascade, lipid metabolism, and neuroimmune modulation. However, the cell-specific effect of variants in these genes is not fully understood. Here, we perform single-nucleus RNA-sequencing (snRNA-seq) on nearly 300,000 nuclei from the parietal cortex of AD autosomal dominant (
APP
and
PSEN1
) and risk-modifying variant (
APOE, TREM2
and
MS4A
) carriers. Within individual cell types, we capture genes commonly dysregulated across variant groups. However, specific transcriptional states are more prevalent within variant carriers.
TREM2
oligodendrocytes show a dysregulated autophagy-lysosomal pathway,
MS4A
microglia have dysregulated complement cascade genes, and
APOE
ε4 inhibitory neurons display signs of ferroptosis. All cell types have enriched states in autosomal dominant carriers. We leverage differential expression and single-nucleus ATAC-seq to map GWAS signals to effector cell types including the
NCK2
signal to neurons in addition to the initially proposed microglia. Overall, our results provide insights into the transcriptional diversity resulting from AD genetic architecture and cellular heterogeneity. The data can be explored on the online browser (
http://web.hararilab.org/SNARE/
).
Mutations in amyloid precursor protein (APP) and presenilin 1 (PSEN1) cause autosomal dominant AD (ADAD). Here, the authors perform single-nucleus RNA-sequencing of ADAD and other disease risk modifying variant carriers and report altered expression states of specific brain cell types.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
