Regulated trafficking of APP by SORLA in Alzheimer’s disease

Angelyn R. Lao

College

College of Science

Department/Unit

Mathematics and Statistics Department

Document Type

Report

Publication Date

2012

Abstract

Proteolytic breakdown of the amyloid precursor protein (APP) by secretases is a complex cellular process that results in formation of neurotoxic Aβ 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. This study aims to (i) model the neuronal factors central to the proteolytic processing of amyloid precursor protein (APP),(ii) trace the trafficking of APP in various compartments, and (iii) evaluate the influence of the SORLA on those factors.

Using experimental data and literature-based, information 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. Our model enables regulation of trafficking of APP by SORLA through intracellular compartments. We have successfully confirmed our hypothesis that blockade of APP dimerization is an important aspect of SORLA action on AD. 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.

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Disciplines

Mathematics

Keywords

Amyloid beta-protein precursor—Mathematical models; Alzheimer's disease

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