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; Melissa E. Murray

doi:10.1038/s41467-021-22399-3

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 AllenMinerva M. Carrasquillo, Hu Li, Owen A. Ross, Nilüfer Ertekin-Taner, Dennis W. Dickson, Yan W. Asmann, Rickey E. Carter, Melissa E. Murray

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	2311
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22399-3
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Crist, A. M., Hinkle, K. M., Wang, X., Moloney, C. M., Matchett, B. J., Labuzan, S. A., Frankenhauser, I., Azu, N. O., Liesinger, A. M., Lesser, E. R., Serie, D. J., Quicksall, Z. S., Patel, T. A., Carnwath, T. P., DeTure, M., Tang, X., Petersen, R. C., Duara, R., Graff-Radford, N. R., ... Murray, M. E. (2021). Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease. Nature communications, 12(1), Article 2311. https://doi.org/10.1038/s41467-021-22399-3

Crist, AM, Hinkle, KM, Wang, X, Moloney, CM, Matchett, BJ, Labuzan, SA, Frankenhauser, I, Azu, NO, Liesinger, AM, Lesser, ER, Serie, DJ, Quicksall, ZS, Patel, TA, Carnwath, TP, DeTure, M, Tang, X, Petersen, RC, Duara, R, Graff-Radford, NR, Allen, M, Carrasquillo, MM , Li, H , Ross, OA , Ertekin-Taner, N , Dickson, DW , Asmann, YW , Carter, RE & Murray, ME 2021, 'Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease', Nature communications, vol. 12, no. 1, 2311. https://doi.org/10.1038/s41467-021-22399-3

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abstract = "Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer{\textquoteright}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.",

author = "Crist, {Angela M.} and Hinkle, {Kelly M.} and Xue Wang and Moloney, {Christina M.} and Matchett, {Billie J.} and Labuzan, {Sydney A.} and Isabelle Frankenhauser and Azu, {Nkem O.} and Liesinger, {Amanda M.} and Lesser, {Elizabeth R.} and Serie, {Daniel J.} and Quicksall, {Zachary S.} and Patel, {Tulsi A.} and Carnwath, {Troy P.} and Michael DeTure and Xiaojia Tang and Petersen, {Ronald C.} and Ranjan Duara and Graff-Radford, {Neill R.} and Mariet Allen and Carrasquillo, {Minerva M.} and Hu Li and Ross, {Owen A.} and Nil{\"u}fer Ertekin-Taner and Dickson, {Dennis W.} and Asmann, {Yan W.} and Carter, {Rickey E.} and Murray, {Melissa E.}",

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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.

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

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