Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease

Angela M. Crist, Kelly M. Hinkle, Xue Wang, Christina M. Moloney, Billie J. Matchett, Sydney A. Labuzan, Isabelle Frankenhauser, Nkem O. Azu, Amanda M. Liesinger, Elizabeth R. Lesser, Daniel J. Serie, Zachary S. Quicksall, Tulsi A. Patel, Troy P. Carnwath, Michael DeTure, Xiaojia Tang, Ronald C. Petersen, Ranjan Duara, Neill R. Graff-Radford, Mariet Allen, Minerva M. Carrasquillo, Hu Li, Owen A. Ross, Nilüfer Ertekin-Taner, Dennis W. Dickson, Yan W. Asmann, Rickey E. Carter and Melissa E. Murray ()
Additional contact information
Angela M. Crist: Department of Neuroscience, Mayo Clinic
Kelly M. Hinkle: Department of Neuroscience, Mayo Clinic
Xue Wang: Department of Health Sciences Research, Mayo Clinic
Christina M. Moloney: Department of Neuroscience, Mayo Clinic
Billie J. Matchett: Department of Neuroscience, Mayo Clinic
Sydney A. Labuzan: Department of Neuroscience, Mayo Clinic
Isabelle Frankenhauser: Department of Neuroscience, Mayo Clinic
Nkem O. Azu: Department of Neuroscience, Mayo Clinic
Amanda M. Liesinger: Department of Neuroscience, Mayo Clinic
Elizabeth R. Lesser: Department of Health Sciences Research, Mayo Clinic
Daniel J. Serie: Department of Health Sciences Research, Mayo Clinic
Zachary S. Quicksall: Department of Health Sciences Research, Mayo Clinic
Tulsi A. Patel: Department of Neuroscience, Mayo Clinic
Troy P. Carnwath: Department of Neuroscience, Mayo Clinic
Michael DeTure: Department of Neuroscience, Mayo Clinic
Xiaojia Tang: Department of Health Sciences Research, Mayo Clinic
Ronald C. Petersen: Department of Neurology, Mayo Clinic
Ranjan Duara: Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center
Neill R. Graff-Radford: Department of Neurology, Mayo Clinic
Mariet Allen: Department of Neuroscience, Mayo Clinic
Minerva M. Carrasquillo: Department of Neuroscience, Mayo Clinic
Hu Li: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic
Owen A. Ross: Department of Neuroscience, Mayo Clinic
Nilüfer Ertekin-Taner: Department of Neuroscience, Mayo Clinic
Dennis W. Dickson: Department of Neuroscience, Mayo Clinic
Yan W. Asmann: Department of Health Sciences Research, Mayo Clinic
Rickey E. Carter: Department of Health Sciences Research, Mayo Clinic
Melissa E. Murray: Department of Neuroscience, Mayo Clinic

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer’s disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.

Date: 2021
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DOI: 10.1038/s41467-021-22399-3

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