Abstract
Alzheimer's disease (AD) is the most common form of dementia and leads to irreversible neurodegenerative damage of the brain. Finding the dynamic responses of genes, signaling proteins, transcription factor (TF) activities, and regulatory networks of the progressively deteriorative progress of AD would represent a significant advance in discovering the pathogenesis of AD. However, the high throughput technologies of measuring TF activities are not yet available on a genome-wide scale. In this study, based on DNA microarray gene expression data and a priori information of TFs, network component analysis (NCA) algorithm is applied to determining the TF activities and regulatory influences on TGs of incipient, moderate, and severe AD. Based on that, the dynamical gene regulatory networks of the deteriorative courses of AD were reconstructed. To select significant genes which are differentially expressed in different courses of AD, independent component analysis (ICA), which is better than the traditional clustering methods and can successfully group one gene in different meaningful biological processes, was used. The molecular biological analysis showed that the changes of TF activities and interactions of signaling proteins in mitosis, cell cycle, immune response, and inflammation play an important role in the deterioration of AD.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease with an insidious onset and progressive stage that inevitably leads to death
To evaluate independent component analysis (ICA) applied to AD DNA gene expression data, we use the dataset of hippocampal gene expression of control and AD samples from GEO DataSets, series GSE1297, offered by Blalock et al [27]
Two inputs were prepared for network component analysis (NCA) model: one was matrix [E], which presented the gene expression profiles of TGs provided by the original gene expression data of AD, and the other was predefined initial matrix [C0] which reflected the relative contribution of the transcription factor (TF) on TGs
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease with an insidious onset and progressive stage that inevitably leads to death. The disease progression of AD is slow, and it may take several years from onset of cognitive decline to diagnosis. Discovering the changes of gene expressions, transcriptional factors (TFs), and the transcriptional regulatory mechanism, which maps out the coordinated dynamic response of TFs and TGs, would provide a significant advance in genome-wide analysis of AD. The characteristic pathology change in AD is fibrin deposition in cerebral cortex, and it is the deposition of beta-amyloid (Aβ) in cell space and poly-Tau protein in cell. The main-stream theory regarding the disease mechanism is the amyloid cascade hypothesis [2]. Ray et al found 18 signaling proteins, which can efficiently classify AD and control subjects, in blood. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis, and neuronal support in presymptomatic AD [4].
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