TY - JOUR
T1 - Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease
AU - Crist, Angela M.
AU - Hinkle, Kelly M.
AU - Wang, Xue
AU - Moloney, Christina M.
AU - Matchett, Billie J.
AU - Labuzan, Sydney A.
AU - Frankenhauser, Isabelle
AU - Azu, Nkem O.
AU - Liesinger, Amanda M.
AU - Lesser, Elizabeth R.
AU - Serie, Daniel J.
AU - Quicksall, Zachary S.
AU - Patel, Tulsi A.
AU - Carnwath, Troy P.
AU - DeTure, Michael
AU - Tang, Xiaojia
AU - Petersen, Ronald C.
AU - Duara, Ranjan
AU - Graff-Radford, Neill R.
AU - Allen, Mariet
AU - Carrasquillo, Minerva M.
AU - Li, Hu
AU - Ross, Owen A.
AU - Ertekin-Taner, Nilüfer
AU - Dickson, Dennis W.
AU - Asmann, Yan W.
AU - Carter, Rickey E.
AU - Murray, Melissa E.
N1 - Funding Information:
This study was supported by the National Institute on Aging (R01 AG054449, U01 AG057195, P01 AG003949, P30 AG062677, P50 AG047266, U01 AG006786, and R01 AG034676), the Florida Department of Health, Ed and Ethel Moore Alzheimer’s Disease Research Program (6AZ01, 8AZ06, 20A22), and the Alzheimer’s Association (AARG-17-533458). We would like to thank Peter Davies for providing the CP13 antibody, Shu-Hui Yen for Ab39 antibody, Leonard Petrucelli and Casey Cook for the E1 antibody, and Pritam Das for the 33.1.1 antibody. We are grateful to Ariston L. Librero, Jo Landino, and Virginia Phillips for histological support; to Monica Castanedes‐Casey for immunohistochemical support; and to our brain bank study coordinators Rachel LaPaille-Harwood and Jessica F. Tranovich. This work would not be possible without the generosity of the Gerstner Family Career Development Award, Center of Individualized Medicine at Mayo Clinic, and a kind gift from David and Frances Strawn. We thank the patients and their families for their generous brain donations to help further our knowledge of Alzheimer’s disease. This work was supported by National Institute on Aging (U01 AG046139, RF1 AG051504 to N.E.T.); National Institute of Neurological Disorders and Stroke (R01 NS080820 to N.E.T.). Study data were provided by the following sources: The Mayo Clinic Alzheimer’s Disease Genetic Studies, led by Dr. Nilüfer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL, using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer’s Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P30 AG062677, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson’s Disease Consortium), and the Michael J. Fox Foundation for Parkinson’s Research. The results published here are in whole or in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.synapse.org/, Synapse IDs: syn17010685, syn3163039, syn20801188). These data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine.
Funding Information:
R.C.P. is a consultant for Hoffman-La Roche, Merck, Biogen, Eisai. R.C.P. is on the Data safety and monitoring board for Genentech. N.G.R. takes part in multi-center studies funded by Lilly, Biogen, and Abbvie. M.E.M. served as a consultant for AVID Radiopharmaceuticals. All other authors declare no competing interests.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-22399-3
DO - 10.1038/s41467-021-22399-3
M3 - Article
C2 - 33875655
AN - SCOPUS:85104548996
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2311
ER -