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


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 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.
Department of Systems Biology and Bioinformatics, Institute of Computer Science, University of Rostock, Germany.
Angelyn
A
Lao
Vanessa
V
Schmidt
Yvonne
Y
Schmitz
Thomas E
TE
Willnow
Olaf
O
Wolkenhauer
D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008954:Models, Biological; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D059748:Proteolysis; D012307:Risk Factors; D012995:Solubility
D016564:Amyloid beta-Protein Precursor; D026901:Membrane Transport Proteins; D053829:Amyloid Precursor Protein Secretases