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 thein silicoobservationsin 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.
Highlights
Alzheimer disease (AD) is the most common cause of dementia worldwide, affecting the elderly population, characterized by the hallmark pathology of amyloid-β (Aβ) deposition and neurofibrillary tangle (NFT) formation in the brain
The extracted network showed again the most significant relationship with transcriptional regulation by cAMP-response element-binding protein (CREB) with the score of 71 and score (p) = 3.325E-022, comprised of 5 upregulated and 5 downregulated incipient AD-related genes (IADGs) (Fig. 4 and Table 1). These results suggest that functional impairment of CREB in the AD hippocampus is beginning at the early stage of the disease
By using KeyMolnet, we characterized the molecular network of 2,883 AD-related genes (ADGs) and 559 IADGs that show significant correlations with MiniMental State Examination (MMSE) score and NFT burden in either all stages of AD or the early stage of AD [10]
Summary
Alzheimer disease (AD) is the most common cause of dementia worldwide, affecting the elderly population, characterized by the hallmark pathology of amyloid-β (Aβ) deposition and neurofibrillary tangle (NFT) formation in the brain. Global transcriptome analysis of AD brains identified a battery of genes aberrantly regulated in AD, whose role has not been previously. J. Satoh et al / Aberrant CREB-mediated gene regulation in the Alzheimer disease predicted in its pathogenesis. Satoh et al / Aberrant CREB-mediated gene regulation in the Alzheimer disease predicted in its pathogenesis They include reduced expression of kinases/phosphatases, cytoskeletal proteins, synaptic proteins, and neurotransmitter receptors in NFT-bearing CA1 neurons [3], downregulaton of neurotrophic factors and upregulation of proapoptotic molecules in the hippocampal CA1 region [4], disturbed sphingolipid metabolism in various brain regions during progression of AD [5], and overexpression of the AMPA receptor GluR2 subunit in synaptosomes of prefrontal cortex [6]. Cardinal observations obtained from in silico data analysis should be validated by independent wet lab experiments
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