Computational Modelling and Analysis of Neuronal Pathways in Alzheimer’s

Abstract

Alzheimer’s is a progressive neurodegenerative disease which damages the brain of elderly population. It is a silent progressive disease and establishes over time with the formation of senile plaques and neurofibrillary tangles in the brain. There is an imbalance in production and clearance of amyloid beta (Aβ) mechanism which aggregates into senile plaques. A key challenge in Alzheimer’s diagnosis is to unravel this mechanism of production and aggregation of Aβ leading to neuronal cell death. The study focuses on key neuronal pathways involved in senile plaques formation, in order to identify adequate therapeutic targets for diagnosis, prognosis and treatment. The main pathways which play role in progression of Alzheiemr’s are Calpain-Calpastatin (CAST) regulation system, Amyloid Precursor Protein (APP) processing pathways (Amyliodogenic and Non Amyloidogenic), Protein Kinase C (PKC) pathway along with Ca2+ channels. This work is aimed to provide clear understanding on the role of these pathways in physiological and pathophysiological conditions. A systematic methodology is employed to construct stochastic Petri net models for understanding dynamics of pathways. The model of Ca2+ channels show homeostatic behaviour in brain. The model of APP processing pathways reveals that Aβ aggregation is minute and the aggregation takes eighty years or more to appear in healthy brain. The calpain-CAST pathway model shows that under physiological conditions, calpain over activation is controlled by CAST in the form of complexes and Ca2+ homeostasis is also observed. The crosstalk model of these pathways reveals that Aβ accumulation starts at early age (40 years). It is also observed that Aβ accumulation first enters lag phase of 20 years then rapid aggregation (growth phase) appears after 60 years of age. All the related patho-physiological events such as dysregulation of Ca2+ homeostasis, calpain hyper-activation, CAST degradation and abnormal digestion of APP are observed in the model. An important prediction of the model is that calpain is the main agent of dysregulation which trigger all the other events such as rise in Ca2+ levels in the cytosol, Aβ aggregation and CAST depletion. An intervention is also proposed that stability of calpain-CAST complexes controls neuro degradation and restricts pathophysiological events. The study on these neurological network is further extended by focusing on the roles of calpain-CAST regulation system in our body. The network is reduced to key proteins such as calpain, CAST, Ca2+ channels and PKC. An abstracted qualitative model is constructed which reveals homeostasis and x epigenetic behaviour. Ca2+ homeostasis is maintained along with oscillation of CAST and PKC. Calpain proves to be fatal which upon activation destroys the homeostasis of Ca2+ and other proteins. PKC is unique in the system, it has influenced both physiological and pathophysiological events by providing extra support to calpain-CAST complexes. The study is further extended by structural exploration and refinement of calpain protein to utilize it for computational drug designing in future. A molecular dynamics (MD) study is designed to correct the mutated crystallized active structure of the protein. The structure is re-mutated to stabilized form and it is then subjected to extensive MD simulations to study the effects of mutation, role of bound Ca2+ ions and to monitor stability in two solvent models. A mutated and stabilized structure of calpain is obtained which can be used by scientists for drug designing studies on the protein.