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Multi-compartmental modeling of SORLA's influence on amyloidogenic processing in Alzheimer's disease

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Item Type:Article
Title:Multi-compartmental modeling of SORLA's influence on amyloidogenic processing in Alzheimer's disease
Creators Name:Lao, A. and Schmidt, V. and Schmitz, Y. and Willnow, T.E. and Wolkenhauer, O.
Abstract:BACKGROUND: Proteolytic breakdown of the amyloid precursor protein (APP) by secretases is a complex cellular process that results in formation of neurotoxic Aß peptides, causative of neurodegeneration in Alzheimer's disease (AD). Processing involves monomeric and dimeric forms of APP that traffic through distinct cellular compartments where the various secretases reside. Amyloidogenic processing is also influenced by modifiers such as sorting receptor-related protein (SORLA), an inhibitor of APP breakdown and major AD risk factor. RESULTS: In this study, 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 dimers, the preferred secretase substrate. In addition, SORLA alters the dynamic behavior of beta-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 beta-secretase as the two distinct targets of the inhibitory action of SORLA in Alzheimer's disease.
Keywords:Amyloidogenic Processing, Compartmental Modeling, LR11, Secretases, SORL1, VPS10P, Domain Receptors
Source:BMC Systems Biology
Publisher:BioMed Central
Page Range:74
Date:22 June 2012
Official Publication:https://doi.org/10.1186/1752-0509-6-74
PubMed:View item in PubMed

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