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A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain

Jorge L. Del-Aguila, Zeran Li, Umber Dube, Kathie A. Mihindukulasuriya, John P Budde, Maria Victoria Fernandez, Laura Ibanez, Joseph Bradley, Fengxian Wang, Kristy Bergmann, Richard Davenport, John C. Morris, David M. Holtzman, Richard J. Perrin, Bruno A. Benitez, View ORCID ProfileJoseph Dougherty, Carlos Cruchaga, Oscar Harari
doi: https://doi.org/10.1101/593756
Jorge L. Del-Aguila
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
dNeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis
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Zeran Li
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
dNeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis
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Umber Dube
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
dNeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis
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Kathie A. Mihindukulasuriya
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
dNeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis
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John P Budde
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
dNeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis
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Maria Victoria Fernandez
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
dNeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis
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Laura Ibanez
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
dNeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis
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Joseph Bradley
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
dNeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis
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Fengxian Wang
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
dNeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis
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Kristy Bergmann
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
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Richard Davenport
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
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John C. Morris
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
cKnight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
eDepartment of Neurology, Washington University School of Medicine, St. Louis, MO, USA
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David M. Holtzman
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
cKnight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
eDepartment of Neurology, Washington University School of Medicine, St. Louis, MO, USA
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Richard J. Perrin
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
cKnight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
fDepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Bruno A. Benitez
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
dNeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis
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Joseph Dougherty
gDepartment of Genetics, Washington University School of Medicine, St. Louis, MO, USA
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  • ORCID record for Joseph Dougherty
Carlos Cruchaga
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
cKnight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
dNeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis
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  • For correspondence: cruchagac@wustl.edu harario@wustl.edu
Oscar Harari
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
bHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
cKnight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
dNeuroGenomics and Informatics, Department of Psychiatry Washington University in St. Louis
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  • For correspondence: cruchagac@wustl.edu harario@wustl.edu
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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.

Footnotes

  • Jorge L Del-Aguila: del-aguila{at}wustl.edu, Zeran Li: zeranli{at}wustl.edu, Umber Dube: udube{at}wustl.edu,Kathie A. Mihindukulasuriya: mihindu{at}wustl.edu, John P Budde: budde{at}wustl.edu, Maria Victoria Fernandez: fernandezv{at}wustl.edu, Laura Ibanez: ibanezl{at}wustl.edu, Joseph Bradley: josephbradley{at}wustl.edu, Fengxian Wang: wang.fengxian{at}wustl.edu, Kristy Bergmann: k.bergmann{at}wustl.edu, Richard Davenport: r.davenport{at}wustl.edu, John C. Morris: jcmorris{at}wustl.edu, David M. Holtzman: holtzman{at}wustl.edu, Richard J. Perrin: rperrin{at}wustl.edu, Bruno A. Benitez: babenitez{at}wustl.edu, Joseph Dougherty: jdougherty{at}wustl.edu

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Posted April 18, 2019.
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A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain
Jorge L. Del-Aguila, Zeran Li, Umber Dube, Kathie A. Mihindukulasuriya, John P Budde, Maria Victoria Fernandez, Laura Ibanez, Joseph Bradley, Fengxian Wang, Kristy Bergmann, Richard Davenport, John C. Morris, David M. Holtzman, Richard J. Perrin, Bruno A. Benitez, Joseph Dougherty, Carlos Cruchaga, Oscar Harari
bioRxiv 593756; doi: https://doi.org/10.1101/593756
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A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain
Jorge L. Del-Aguila, Zeran Li, Umber Dube, Kathie A. Mihindukulasuriya, John P Budde, Maria Victoria Fernandez, Laura Ibanez, Joseph Bradley, Fengxian Wang, Kristy Bergmann, Richard Davenport, John C. Morris, David M. Holtzman, Richard J. Perrin, Bruno A. Benitez, Joseph Dougherty, Carlos Cruchaga, Oscar Harari
bioRxiv 593756; doi: https://doi.org/10.1101/593756

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