Multi-compartmental modeling of APP processing influenced by SORLA in Alzheimer’s disease

The formation of Aβ plaques from the processing of amyloid precursor protein (APP) is central to the pathology of Alzheimer’s disease. Studies concerning APP processing are conventionally conducted in a single-compartment, where the reactants involved are either in a monomeric or a dimeric form of APP. In the single-compartment model we presented earlier, it showed that the sorting receptor-related protein, SORLA, affects APP processing in both its monomeric and dimeric forms. This study raised the interesting question of what the relative contribution of SORLA in each APP processing step is and how this affects the β-secretase. Results: To answer this question, we developed a multi-compartment model to simulate the complexity of APP processing in neurons, and to accurately describe the effects of SORLA on these processes. Based on dose-response data, our study concludes that SORLA specifically impairs processing of APP dimer, which is the preferred secretase substrate. Furthermore, our model shows how SORLA alters the dynamical behavior of β-secretase, the enzyme responsible for the initial step in the amyloidogenic processing cascade. Conclusions: Our multi-compartment model represents a major conceptual advance over single-compartment models previously used to simulate APP processing; and it identified APP dimers and β-secretase as the two distinct targets of the inhibitory action of SORLA in Alzheimer’s disease