Probable interaction networks involved in pathology of Alzheimer’s disease: predicting targets and therapeutic agents-NetProTM based study
Alzheimer disease, the most common cause of senile dementia is a progressive neurodegenerative disease characterized by loss of memory and cognition. The major neuropathologic features of Alzheimer disease (AD) include formation of amyloid plaques and Neurofibrillary tangles in certain regions of the brain. Even a century after the discovery of this disease, the drugs available can only alleviate the disease symptoms but there is no available drug that can actually stop the progression of the disease. The current analysis is aimed at generating an interaction network depicting the plausible molecular events leading to the development of the disease condition and narrowing down on molecules that might be important targets or therapeutic agents for this disease, based on the network generated. Towards this, data from a commercially available bi-molecular interaction database NetProTM that contains high quality manually curated protein-protein and protein-small molecule interactions, was used to understand interaction network(s) of a set of genes, specifically shown to be differentially regulated in Alzheimer disease patients in a microarray study done by Colangelo V et al (2002)1
An interaction network was generated that depicts the highly complex and coordinated regulation of both expression and activities of the molecules that might be of etiological significance. Majority of the genes which were differentially regulated in the disease condition were found to be involved, in one way or the other, either in the generation of Aβ fragment of APP, a major constituent of the amyloid plaques, or in the hyperphosphorylation of Tau, which leads to the formation of neurofibrillary tangles, or in apoptosis leading to neuronal cell death. Importantly these processes seemed to converge on certain molecules like APP, MAPT, TNF, Interleukin1, BDNF, Calcium and transcription factors like NF-kappa-B, CREBP, GATA and PPARG, most of which are known to be important in the course of Alzheimer disease progression2-5
Fig-1: Interaction network depicting the plausible molecular mechanisms leading to Alzheimer disease
Based on the interaction network generated from this analysis we predict a few molecules, which might be of therapeutic importance either as drug targets (TNF, PPARG, BDNF etc) or as therapeutic agents (compounds in fig2). The results from this study suggest that collative affects of more than one factor/molecular network leads to the overall imbalance that culminates in the pathologic manifestation. The drugs currently available targets only one or the other molecular pathway leading to the disease, which explains partly the limitations of the drugs in treating the disease condition. A comprehensive approach taking into consideration the various molecular messengers leading to the development of the disease is required for successful therapy of this dreaded disease. Analysis like this where high throughput data like microarray data are combined with interaction networks from databases to study disease conditions, could prove to be a very effective way of studying the molecular pathogenesis of the diseases and in predicting possible targets or molecules with therapeutic potential.
Fig 2: Network depicting probable target genes and potential therapeutic agents (potential targets indicated by arrow)
Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. Colangelo V et al. 2002; J Neurosci Res. Nov 1; 70(3): 462-73.
Stage-dependent BDNF serum concentrations in Alzheimer's disease. Laske C et al. 2006; J Neural Transm. Sep; 113(9): 1217-24.
Basal and activated intracellular calcium ion concentrations in mononuclear cells of Alzheimer's disease and unipolar depression. Adunsky A et al. 1995; J Gerontol A Biol Sci Med Sci. Jul; 50(4): B201-4.
Role of peroxisome proliferator-activated receptor gamma in amyloid precursor protein processing and amyloid beta-mediated cell death. d'Abramo C et al. 2005; Biochem J. Nov 1; 391(Pt 3): 693-8.
Elevated circulating tumor necrosis factor levels in Alzheimer's disease. Fillit H et al. 1991; Neurosci Lett. Aug 19; 129(2): 318-20.