Analyzing the Behavior of Neuronal Pathways in Alzheimer's Disease Using Petri Net Modeling Approach.

Javaria Ashraf,Zaheer Ul-Haq,Jamil Ahmad,Amjad Ali

doi:10.3389/fninf.2018.00026

Abstract

Alzheimer's Disease (AD) is the most common neuro-degenerative disorder in the elderly that leads to dementia. The hallmark of AD is senile lesions made by abnormal aggregation of amyloid beta in extracellular space of brain. One of the challenges in AD treatment is to better understand the mechanism of action of key proteins and their related pathways involved in neuronal cell death in order to identify adequate therapeutic targets. This study focuses on the phenomenon of aggregation of amyloid beta into plaques by considering the signal transduction pathways of Calpain-Calpastatin (CAST) regulation system and Amyloid Precursor Protein (APP) processing pathways along with Ca2+ channels. These pathways are modeled and analyzed individually as well as collectively through Stochastic Petri Nets for comprehensive analysis and thorough understating of AD. The model predicts that the deregulation of Calpain activity, disruption of Calcium homeostasis, inhibition of CAST and elevation of abnormal APP processing are key cytotoxic events resulting in an early AD onset and progression. Interestingly, the model also reveals that plaques accumulation start early (at the age of 40) in life but symptoms appear late. These results suggest that the process of neuro-degeneration can be slowed down or paused by slowing down the degradation rate of Calpain-CAST Complex. In the light of this study, the suggestive therapeutic strategy might be the prevention of the degradation of Calpain-CAST complexes and the inhibition of Calpain for the treatment of neurodegenerative diseases such as AD.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder which has impacted nearly 44 million1 people around the world and this number is still increasing
Calpain slowly degrades CAST which depletes from the cell and eventually neuronal degradation progresses. These results suggest that patho-physiological events such as dysregulation of Ca2+ homeostasis, Calpain hyperactivation, CAST degradation and abnormal digestion of Amyloid Precursor Protein (APP), all are inter-connected and a cumulative study of these processes through Stochastic petri nets (SPNs) was needed
Calpain triggers the production of P35 and the degradation of CAST and PKC

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder which has impacted nearly 44 million people around the world and this number is still increasing. AD establishes over time with the appearance of pathological emblems which are senile plaques and neurofibrillary tangles These lesions comprise of extracellular deposits of Amyloid beta (Aβ) (Selkoe, 2000; Golde, 2005; Tam and Pasternak, 2012) and intracellular selfgathered clumps of tau proteins (Lee et al, 2001), respectively. The first step of non-amyloidogenic pathway is carried out by the enzyme alpha (α)-secretase that breaks down APP into soluble Amyloid precursor protein alpha (sAPPα) and alpha C-terminal fragment (αCTF / CTF83). The catalysis by αsecretase is imperative as it cuts APP within Aβ domain which blocks Aβ formation (Lichtenthaler, 2011) This initial step can be driven by the beta (β)-secretase / β-site APP-cleaving enzyme (BACE), a transmembrane aspartyl protease (Vassar et al, 1999; Haass, 2004) (Figure 1), which constitute amyloidogenic pathway. Γ -secretase degrades the βCTF into Aβ and AICD (O’Brien and Wong, 2011) (Figure 1)

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