Computational Investigations and Experimental Validation of Alzheimers Disease Related Pathways With Special Relevance to Dna Repair and Autophagy

Abstract

Alzheimer’s disease (AD), also known as senile dementia, is a neurodegenerative disease and the most common form of chronic dementia that shows progressive loss of memory, synaptic function, cognitive capacity and atrophy in different brain areas in the elderly. Epidemiological studies highlighted AD as a multifactorial disease i.e.; it occurs due to complex interactions between various intrinsic and extrinsic factors. The pathology of AD involves a combination of intrinsic genomic susceptibility and environmental factors. It entails a continual dynamic interplay between dysfunctional pathways and central homeostatic networks of nerve cells. The neuropathological changes of AD include Aβ plaques and neurofibrillary tangles (NFT). Innumerable evidences suggest that an autophagy-or DNA damage and repair (DDR) pathway-dysfunction further promote Aβ plaques and NFT. Employing a systems biology approach to integrate protein alterations provides link between multiple molecular abnormalities leading to memory impairment revealing a broadly dispersed and multi-molecular targeting pathogenic process. Both DDR pathway and autophagy process hold constitutive role in AD. We have retrieved several pathways related to DNA damage, DNA repair and autophagy from the STRING, KEGG and other databases. All this information was compiled carefully to implement further analysis. We have created a Protein-protein interaction (PPI) network and then that network has been analyzed using Cytoscape to explore the role of these integrations. Further, a virtual electronic cell (E-cell) was built to study the interaction of these proteins and analyzed using Cytoscape. Topological features of the network analysis were used to interpret the model under study and determine hub proteins. Through in-vitro experimentation, the model was further validated by studying the role of the hub proteins on Neuro 2A cell line.