Figure 1
From: Multi-compartmental modeling of SORLA’s influence on amyloidogenic processing in Alzheimer’s disease
Biochemical network of a multi-compartmental model describing the influence of SORLA in APP processing. The three main yellow compartments in the network are the trans-Golgi network (TGN), the cell surface and the endosomes. Each compartment is subdivided into two subcompartments: a red subcompartment for APP monomer processing and a green one for dimer processing. The monomeric forms of APP, SORLA, α-secretase, and β-secretase, within the two subcompartments, are annotated differently: APP G1 , SORLA G1 , α 1 , and β 1 for monomer processing, and APP G2 , SORLA G2 , α 2 , and β 2 for dimer processing. Moreover, APP G2 , α 2 , and β 2 undergo dimerization before the start of APP processing. In the TGN, SORLA G1 binds to APP G1 in red subcompartment while SORLA G2 to APP G2 in the green subcompartment. At the cell surface, APP CS1 and APP CS2d are cleaved by α 1 and α 2d producing soluble fragments encompassing the extracellular domain of APP. These fragments are called soluble (s) sAPPα 1 and sAPPα 2 , respectively. In addition, α-secretase cleavage produces a membrane-associated fragment containing the membrane anchor and the cytoplasmic tail, denoted C83. In the endosomes, APP molecules that escaped cleavage by α-secretase (APP E1 and APP E2d ) are cleaved by β 1 and β 2d . Cleavage results in production of the soluble fragments of the extracellular APP domain (sAPPβ 1 and sAPPβ 2 ) and in the membrane-tethered fragments C99 1 and C99 2d . C99 includes the Aβ peptide sequence and represents the substrate for γ-secretase cleavage. The diagram was produced with Cell Designer 4.0[18, 19].