Affiliations: Department of Bioinformatics and Molecular
Neuropathology, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo
204-8588, Japan | Department of Psychiatry, National Center Hospital,
National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo
187-8551, Japan
Note: [] Corresponding author: Prof. Dr. Jun-ichi Satoh, Department of
Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University,
2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan. Tel./Fax: +81 42 495 8678;
E-mail: satoj@my-pharm.ac.jp
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.
