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Mol Neurodegener. 2016 Apr 26;11:31. doi: 10.1186/s13024-016-0095-2.

Network-driven plasma proteomics expose molecular changes in the Alzheimer's brain.

Author information

1
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. pjaeger@ucsd.edu.
2
Institute of Chemistry and Biochemistry, Free University Berlin, Berlin, Germany. pjaeger@ucsd.edu.
3
Departments of Bioengineering and Medicine, University of California San Diego, La Jolla, CA, USA. pjaeger@ucsd.edu.
4
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
5
Present address: Biology Department, Eastern Connecticut State University, Willimantic, CT, USA.
6
Present address: Roche Pharma Research and Early Development, NORD DTA, Roche Innovation, Center Basel, Basel, Switzerland.
7
Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA.
8
RayBiotech, Guangzhou, China.
9
RayBiotech, Norcrosse, GA, USA.
10
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
11
Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
12
Departments of Neurology, Ophthalmology, Genetics and Genomics, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
13
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
14
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
15
Departments of Pharmacology and Nutritional Sciences and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
16
Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA.
17
Genetics and Pharmacogenomics, Merck Research Laboratories, West Point, PA, USA.
18
Department of Pathology, University of California San Diego, La Jolla, CA, USA.
19
Departments of Bioengineering and Medicine, University of California San Diego, La Jolla, CA, USA.
20
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. twc@stanford.edu.
21
Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System, Palo Alto, CA, USA. twc@stanford.edu.

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.

PMID:
27112350
PMCID:
PMC4845325
DOI:
10.1186/s13024-016-0095-2
[Indexed for MEDLINE]
Free PMC Article

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