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PMID: 18256261 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural

A systems level analysis of transcriptional changes in Alzheimer's disease and normal aging.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 28 ·No. 6 ·2008-02-06 ·Pages 1410-20

Miller JA, Oldham MC, Geschwind DH

Abstract

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder affecting millions of elderly individuals worldwide. Advances in the genetics of AD have led to new levels of understanding and treatment opportunities. Here, we used a systems biology approach based on weighted gene coexpression network analysis to determine transcriptional networks in AD. This method permits a higher order depiction of gene expression relationships and identifies modules of coexpressed genes that are functionally related, rather than producing massive gene lists. Using this framework, we characterized the transcriptional network in AD, identifying 12 distinct modules related to synaptic and metabolic processes, immune response, and white matter, nine of which were related to disease progression. We further examined the association of gene expression changes with progression of AD and normal aging, and were able to compare functional modules of genes defined in both conditions. Two biologically relevant modules were conserved between AD and aging, one related to mitochondrial processes such as energy metabolism, and the other related to synaptic plasticity. We also identified several genes that were central, or hub, genes in both aging and AD, including the highly abundant signaling molecule 14.3.3 zeta (YWHAZ), whose role in AD and aging is uncharacterized. Finally, we found that presenilin 1 (PSEN1) is highly coexpressed with canonical myelin proteins, suggesting a role for PSEN1 in aspects of glial-neuronal interactions related to neurodegenerative processes.

MeSH Terms
Adult Aged Aged, 80 and over Aging/genetics,metabolism Alzheimer Disease/genetics,pathology,physiopathology Gene Expression Profiling/methods Hippocampus/pathology,physiology Humans Middle Aged Presenilin-1/biosynthesis,genetics,physiology Systems Biology/methods Transcription, Genetic/genetics
Chemicals
PSEN1 protein, human Presenilin-1
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Miller Jeremy A
Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, California 90095-1769, USA.
Oldham Michael C
Geschwind Daniel H
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.4098-07.2008
Published
2008-02-06
Pages
1410-20
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC2902235
Subset
IM
Grants
NIMH NIH HHS · T32 MH073526 · United States
NIMH NIH HHS · T32 MH073526-01A1 · United States
NIA NIH HHS · U01 AG016976 · United States
NIA NIH HHS · F31 AG031649-01 · United States
NIA NIH HHS · R01 AG026938 · United States
NIA NIH HHS · R01 AG026938-01 · United States
NIA NIH HHS · R01 AG26938 · United States
NIMH NIH HHS · T32MH073526-01A1 · United States
NIA NIH HHS · F31 AG031649 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.4098-07.2008 PMC Full Text View journal details
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