Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers.

Autor: Brase L; Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; NeuroGenomics and Informatics, Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., You SF; Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; NeuroGenomics and Informatics, Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., D'Oliveira Albanus R; Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; NeuroGenomics and Informatics, Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Del-Aguila JL; Merck & Co., Inc., Boston, MA, USA., Dai Y; Baylor College of Medicine, Houston, TX, USA., Novotny BC; Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; NeuroGenomics and Informatics, Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Soriano-Tarraga C; Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; NeuroGenomics and Informatics, Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Dykstra T; Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Center for Brain Immunology and Glia (BIG), Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Fernandez MV; Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; NeuroGenomics and Informatics, Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Budde JP; Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; NeuroGenomics and Informatics, Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Bergmann K; Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; NeuroGenomics and Informatics, Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Morris JC; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Knight Alzheimer Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Bateman RJ; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Knight Alzheimer Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Perrin RJ; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Knight Alzheimer Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., McDade E; Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Xiong C; Knight Alzheimer Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Division of Biostatistics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Goate AM; Ronald M. Loeb Center for Alzheimer's Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Farlow M; Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA., Sutherland GT; School of Medical Sciences and Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia., Kipnis J; Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Center for Brain Immunology and Glia (BIG), Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Karch CM; Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; NeuroGenomics and Informatics, Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Benitez BA; Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Harari O; Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA. harario@wustl.edu.; Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, USA. harario@wustl.edu.; NeuroGenomics and Informatics, Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA. harario@wustl.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Apr 21; Vol. 14 (1), pp. 2314. Date of Electronic Publication: 2023 Apr 21.
DOI: 10.1038/s41467-023-37437-5
Abstrakt: 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 APOEε4 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/ ).
(© 2023. The Author(s).)
Databáze: MEDLINE
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