The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration

Abstract

Apoptosis is a programmed cell death that plays a critical role during the development of the nervous system and in many chronic neurodegenerative diseases, including Alzheimer's disease (AD). This pathology, characterized by a progressive degeneration of cholinergic function resulting in a remarkable cognitive decline, is the most common form of dementia with high social and economic impact. Current therapies of AD are only symptomatic, therefore the need to elucidate the mechanisms underlying the onset and progression of the disease is surely needed in order to develop effective pharmacological therapies. Because of its pivotal role in neuronal cell death, apoptosis has been considered one of the most appealing therapeutic targets, however, due to the complexity of the molecular mechanisms involving the various triggering events and the many signaling cascades leading to cell death, a comprehensive understanding of this process is still lacking. Modular systems biology is a very effective strategy in organizing information about complex biological processes and deriving modular and mathematical models that greatly simplify the identification of key steps of a given process. This review aims at describing the main steps underlying the strategy of modular systems biology and briefly summarizes how this approach has been successfully applied for cell cycle studies. Moreover, after giving an overview of the many molecular mechanisms underlying apoptosis in AD, we present both a modular and a molecular model of neuronal apoptosis that suggest new insights on neuroprotection for this disease.

Figure 1

Scheme of the iterative roadmap of computational and experimental approaches applied in modular systems biology.

Figure 2

The basic blueprint of neuronal apoptosis showing the different modules and how they are interconnected by positive and negative feed-backs.

Figure 3

A list of the many genetic and environmental events that contribute to the activation of apoptotic cascades in AD neurodegeneration.

Figure 4

A molecular model of neuronal apoptosis organized in submodules. The central part of the model (green panel) represents the mitochondria submodule and all the molecules that regulate its function as "sensor" of the cellular stress responses (yellow panel). Dark blue and green arrows indicate survival and apoptotic pathways, respectively; orange arrows indicate inhibitions. Red arrows indicate the positive feed-back, while in purple and light blue are indicated the cross-talk between extrinsic/intrinsic apoptotic cascades and the survival regulatory control by IAPs, respectively. More information is the text.

Figure 5

A drawing exemplifying the active "stand-by" status of cells exposed to the various stressful events involved in AD apoptosis. Neuronal death occurs when the cell(s) reaches a point of "No-return", where an overwhelming mitochondria pressure is no longer compensated by the many protective pathways that the cell(s) has adopted.