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Molecular network analysis suggests aberrant CREB-mediated gene regulation in the Alzheimer disease hippocampus.

ABSTRACT: The pathogenesis of Alzheimer disease (AD) involves the complex interaction between genetic and environmental factors affecting multiple cellular pathways. Recent advances in systems biology provide a system-level understanding of AD by elucidating the genome-wide molecular interactions. By using KeyMolnet, a bioinformatics tool for analyzing molecular interactions on the curated knowledgebase, we characterized molecular network of 2,883 all stages of AD-related genes (ADGs) and 559 incipient AD-related genes (IADGs) identified by global gene expression profiling of the hippocampal CA1 region of AD brains in terms of significant clinical and pathological correlations (Blalock et al., Proc Natl Acad Sci USA 101: 2173-2178, 2004). By the common upstream search, KeyMolnet identified cAMP-response element-binding protein (CREB) as the principal transcription factor exhibiting the most significant relevance to molecular networks of both ADGs and IADGs. The CREB-regulated transcriptional network included upregulated and downregulated sets of ADGs and IADGs, suggesting an involvement of generalized deregulation of the CREB signaling pathway in the pathophysiology of AD, beginning at the early stage of the disease. To verify the in silico observations in vivo, we conducted immunohistochemical studies of 11 AD and 13 age-matched control brains by using anti-phoshorylated CREB (pCREB) antibody. An abnormal accumulation of pCREB imunoreactivity was identified in granules of granulovacuolar degeneration (GVD) in the hippocampal neurons of AD brains. These observations suggest that aberrant CREB-mediated gene regulation serves as a molecular biomarker of AD-related pathological processes, and support the hypothesis that sequestration of pCREB in GVD granules is in part responsible for deregulation of CREB-mediated gene expression in AD hippocampus.

SUBMITTER: Satoh J

PROVIDER: S-EPMC3835274 | biostudies-other | 2009

REPOSITORIES: biostudies-other

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Molecular network analysis suggests aberrant CREB-mediated gene regulation in the Alzheimer disease hippocampus.

Satoh Jun-ichi J Tabunoki Hiroko H Arima Kunimasa K

Disease markers 20090101 5

The pathogenesis of Alzheimer disease (AD) involves the complex interaction between genetic and environmental factors affecting multiple cellular pathways. Recent advances in systems biology provide a system-level understanding of AD by elucidating the genome-wide molecular interactions. By using KeyMolnet, a bioinformatics tool for analyzing molecular interactions on the curated knowledgebase, we characterized molecular network of 2,883 all stages of AD-related genes (ADGs) and 559 incipient AD ...[more]

PMID: 20037212

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Project description:Monoamine oxidase-A (MAO-A) and MAO-B have both been implicated in the pathology of Alzheimer disease (AD). We examined 60 autopsied control and AD donor brain samples to determine how well MAO function aligned with two major risk factors for AD, namely sex and APOE ε4 status. MAO-A activity was increased in AD cortical, but not hippocampal, samples. In contrast, MAO-B activity was increased in both regions (with a strong input from female donors) whether sample means were compared based on: (a) diagnosis alone; (b) diagnosis-by-APOE ε4 status (i.e., carriers vs. non-carriers of the ε4 allele); or (c) APOE ε4 status alone (i.e., ignoring 'diagnosis' as a variable). Sample means strictly based on the donor's sex did not reveal any difference in either MAO-A or MAO-B activity. Unexpectedly, we found that cortical MAO-A and MAO-B activities were highly correlated in both males and females (if focussing strictly on the donor's sex), while in the hippocampus, any correlation was lost in female samples. Stratifying for sex-by-APOE ε4 status revealed a strong correlation between cortical MAO-A and MAO-B activities in both non-carriers and carriers of the allele, but any correlation in hippocampal samples was lost in carriers of the allele. A diagnosis of AD disrupted the correlation between MAO-A and MAO-B activities in the hippocampus, but not the cortex. We observed a novel region-dependent co-regulation of MAO-A and MAO-B mRNAs (but not proteins), while a lack of correlation between MAO activities and the respective proteins corroborated previous reports. Overexpression of human APOE4 increased MAO activity (but not mRNA/protein) in C6 and in HT-22 cell cultures. We identified a novel co-regulation of MAO-A and MAO-B activities that is spared from any influence of risk factors for AD or AD itself in the cortex, but vulnerable to these same factors in the hippocampus. Sex- and region-dependent abilities to buffer influences on brain MAO activities could have significant bearing on ambiguous outcomes when monoaminergic systems are targeted in clinical populations.

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Molecular network analysis suggests aberrant CREB-mediated gene regulation in the Alzheimer disease hippocampus.

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Molecular network analysis suggests aberrant CREB-mediated gene regulation in the Alzheimer disease hippocampus.

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