A systems biology approach to understand amyloidogenic processing in Alzheimer's disease: Making sense of data and providing meaning to models

• Main Author: Lao, Angelyn R.
• Format: text
• Published: Animo Repository 2014
• Subjects: Amyloid beta-protein precursor—Mathematical models; Alzheimer's disease; Mathematics
• Online Access: https://animorepository.dlsu.edu.ph/faculty_research/7438
• Institution: De La Salle University

Systems biology is an interdisciplinary approach that aims at understanding the dynamic interactions between components of living system. Using this approach, we have established mathematical models describing the interactome -of neuronal factors central to the proteolytic processing of amyloid precursor protein (APP) into Aβ, the main constituent of senile plaques in Alzheimer's disease (AD). The models were built based a panel of cell lines in which the amount of APP and of accessory factors can be varied. The quantitative dose-response series have been used to estimate reaction constants of mathematical models describing APP processing. The simulations, together with our experimental data, support a model whereby SORLA prevents APP oligomerization, thereby causing secretases to switch from allosteric to non-allosteric mode of action. We also performed simulations for intermediate concentrations of SORLA and predicted a switch from cooperative to less efficient non-cooperative processing on a low amount of SORLA concentration. Using this model, we are able to uncover that SORLA not only affects amyloidogenic processing through interaction with APP but also specifically targets β-secretase - the enzyme responsible for initial amyloidogenic cleavage. Our model represents a major conceptual advancement by identifying APP dimers and β-secretase as the two distinct targets of the inhibitory action of SORLA in AD.