Abstract
Background: Biological pathways that significantly contribute to sporadic Alzheimer’s disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.
Results: To access this information we probed relative levels of close to 600 secreted signaling proteins from patients’ blood samples using antibody microarrays and mapped disease-specific molecular networks. Using these networks as seeds we then employed independent genome and transcriptome data sets to corroborate potential pathogenic pathways.
Conclusions: We identified Growth-Differentiation Factor (GDF) signaling as a novel Alzheimer’s disease-relevant pathway supported by in vivo and in vitro follow-up experiments, demonstrating the existence of a highly informative link between cellular pathology and changes in circulatory signaling proteins.
Document Type
Article
Publication Date
4-26-2016
Digital Object Identifier (DOI)
https://doi.org/10.1186/s13024-016-0095-2
Funding Information
This work was supported by National Institutes of Health (NIH) grants R01AG045034 (TW-C), R01GM084279 (TI), P01HG005062 (TI), P30MH062261 (TI), P41GM103504 (TI), P50AG016574 (Mayo Clinic ADRC), U01AG006786 (BFB, DSK, RCP), R01AG038791 (ALB), P50AG023501 (BLM), P01AG019724 (BLM), P01AG16573 (EH), AG5131/AG/NIA (EM), AG18440/AG/NIA (EM) The Consortium for Frontotemporal Dementia (TW-C), Anonymous (TW-C), The Veterans Administration (TW-C), Tau Research Consortium (ALB), Alzheimer’s Drug Discovery Foundation (ALB), Bluefield Project (ALB).
Repository Citation
Jaeger, Philipp A.; Lucin, Kurt M.; Britschgi, Markus; Vardarajan, Badri; Huang, Ruo-Pan; Kirby, Elizabeth D.; Abbey, Rachelle; Boeve, Bradley F.; Boxer, Adam L.; Farrer, Lindsay A.; Finch, NiCole; Graff-Radford, Neill R.; Head, Elizabeth; Hofree, Matan; Huang, Ruochun; Johns, Hudson; Karydas, Anna; Knopman, David S.; Loboda, Andrey; Masliah, Eliezer; Narasimhan, Ramya; Petersen, Ronald C.; Podtelezhnikov, Alexei; Pradhan, Suraj; Rademakers, Rosa; Sun, Chung-Huan; Younkin, Steven G.; Miller, Bruce L.; Ideker, Trey; and Wyss-Coray, Tony, "Network-Driven Plasma Proteomics Expose Molecular Changes in the Alzheimer's Brain" (2016). Pharmacology and Nutritional Sciences Faculty Publications. 39.
https://uknowledge.uky.edu/pharmacol_facpub/39
Additional file 1
13024_2016_95_MOESM2_ESM.pdf (2603 kB)
Additional file 2
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Notes/Citation Information
Published in Molecular Neurodegeneration, v. 11, 31, p. 1-18.
© Jaeger et al. 2016
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
An erratum to this article can be found at http://dx.doi.org/10.1186/s13024-016-0105-4.