A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain
A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain
Abstract Alzheimer Disease (AD) is the most common form of dementia. This neurodegenerative disorder is associated with neuronal death and gliosis heavily impacting the cerebral cortex. AD has a substantial but heterogeneous genetic component, presenting both Mendelian and complex genetic architectures. Using bulk RNA-seq from parietal lobes and deconvolution methods, we previously reported that brains exhibiting different AD genetic architecture exhibit different cellular proportions. Here, we sought to directly investigate AD brain changes in cell proportion and gene expression using single cell resolution. To do so, we generated unsorted single-nuclei RNA-sequencing data from brain tissue. We leveraged tissue donated from a carrier of a Mendelian genetic mutation and two family members who suffer from AD, but do not have the same mutation. We evaluated alternative alignment approaches to maximize the titer of reads, genes and cells with high quality. In addition, we employed distinct clustering strategies to determine the best approach to identify cell clusters that reveal neuronal and glial cell types and avoid artifacts such as sample and batch effects. We propose an approach to cluster cells that reduces biases and enable further analyses. We identified distinct types of neurons, both excitatory and inhibitory, and glial cells, including astrocytes, oligodendrocytes, and microglia among others. In particular, we identified a reduced proportion of excitatory neurons in the Mendelian mutation carrier, but a similar distribution of inhibitory neurons. Furthermore, we investigated whether single-nuclei RNA-seq from human brains recapitulate the expression profile of Disease Associated Microglia (DAM) discovered in mouse models. We also determined that when analyzing human single-nuclei data it is critical to control for biases introduced by donor specific expression profiles. In conclusion, we propose a collection of best practices to generate a highly-detailed molecular cell atlas of highly informative frozen tissue stored in brain banks. Importantly, we have developed a new web application to make this unique single-nuclei molecular atlas publicly available.
Budde John P、Del-Aguila Jorge L.、Li Zeran、Mihindukulasuriya Kathie A.、Fernandez Maria Victoria、Davenport Richard、Morris John C.、Holtzman David M.、Harari Oscar、Bergmann Kristy、Wang Fengxian、Perrin Richard J.、Bradley Joseph、Ibanez Laura、Benitez Bruno A.、Dube Umber、Cruchaga Carlos、Dougherty Joseph
Department of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of MedicineHope Center for Neurological Disorders, Washington University School of Medicine||Knight Alzheimer?ˉs Disease Research Center||Department of Neurology, Washington University School of MedicineHope Center for Neurological Disorders, Washington University School of Medicine||Knight Alzheimer?ˉs Disease Research Center||Department of Neurology, Washington University School of MedicineDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||Knight Alzheimer?ˉs Disease Research Center||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of MedicineDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisHope Center for Neurological Disorders, Washington University School of Medicine||Knight Alzheimer?ˉs Disease Research Center||Department of Pathology and Immunology, Washington University School of MedicineDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Psychiatry, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||Knight Alzheimer?ˉs Disease Research Center||NeuroGenomics and Informatics, Department of Psychiatry Washington University in St. LouisDepartment of Genetics, Washington University School of Medicine
神经病学、精神病学基础医学分子生物学
PSEN1Single-Nuclei RNAseqAlzheimer’s diseaseWeb-based brain molecular atlas
Budde John P,Del-Aguila Jorge L.,Li Zeran,Mihindukulasuriya Kathie A.,Fernandez Maria Victoria,Davenport Richard,Morris John C.,Holtzman David M.,Harari Oscar,Bergmann Kristy,Wang Fengxian,Perrin Richard J.,Bradley Joseph,Ibanez Laura,Benitez Bruno A.,Dube Umber,Cruchaga Carlos,Dougherty Joseph.A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain[EB/OL].(2025-03-28)[2025-04-24].https://www.biorxiv.org/content/10.1101/593756.点此复制
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