Food Science and Technology Department

 

Authors

Vladislav A. Petyuk, Pacific Northwest National Laboratory
Rui Chang, Icahn School of Medicine at Mount Sinai
Manuel Ramirez-Restrepo, University of Miami Miller School of Medicine
Noam D. Beckmann, Icahn School of Medicine at Mount Sinai
Marc Y. R. Henrion, Icahn School of Medicine at Mount Sinai
Paul D. Piehowski, Pacific Northwest National Laboratory
Kuixi Zhu, Icahn School of Medicine at Mount Sinai
Sven Wang, Icahn School of Medicine at Mount Sinai
Jennifer L. Clarke, University of Nebraska-LincolnFollow
Matthew J. Huentelman, The Translational Genomics Research Institute
Fang Xie, Pacific Northwest National Laboratory
Victor Andreev, Arbor Research Collaborative for Health
Anzhelika Engel, University of Miami Miller School of Medicine
Toumy Guettoche, Roche Sequencing
Loida Navarro, Roche Sequencing
Philip De Jager, Columbia University Medical Center
Julie A. Schneider, Rush University Medical Center
Christopher M. Morris, Newcastle University
Ian G. McKeith, Newcastle University
Robert H. Perry, Royal Victoria Infirmary
Simon Lovestone, University of Oxford
Randall L. Woltjer, Oregon Health and Science University
Thomas G. Beach, Banner Sun Health Research Institute
Lucia I. Sue, Banner Sun Health Research Institute
Geidy E. Serrano, Banner Sun Health Research Institute
Andrew P. Lieberman, University of Michigan
Roger L. Albin, University of Michigan
Isidre Ferrer, University of Barcelona
Deborah C. Mash, University of Miami Miller School of Medicine
Christine M. Hulette, Duke University Medical Center
John F. Ervin, Duke University
Eric M. Reiman, The Arizona Alzheimer’s Consortium
John A. Hardy, University College London Institute of Neurology
David A. Bennett, Rush University Medical Center
Eric Schadt, Icahn School of Medicine at Mount Sinai
Richard D. Smith, Pacific Northwest National Laboratory
Amanda J. Myers, University of Miami Miller School of MedicineFollow

ORCID IDs

Jennifer L. Clarke

Date of this Version

2018

Citation

BRAIN 2018: 141; 2721–2739

Comments

Copyright The Author(s) (2018).

Open access

doi:10.1093/brain/awy215

Abstract

Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65–105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66–107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-B40 and amyloid-B42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer’s disease processes.

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