Sorting Out Presenilins in Alzheimer’s Disease Michael S. Wolfe, Bruce A. Yankner  Cell  Volume 166, Issue 1, Pages 13-15 (June 2016) DOI: 10.1016/j.cell.2016.06.034 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 Sorting of PSEN/γ-Secretase Complexes and Processing of APP to Aβ Peptide PSEN1- and PSEN2-containing proteases are differentially trafficked from the trans-Golgi network. PSEN1/γ-secretase is sorted to the plasma membrane via recycling endosomes. PSEN2/γ-secretase is sorted to late endosomes/lysosomes (LE/LYS) via early endosomes and interaction with AP-1. Aβ is produced from APP first by proteolysis (at site β) through β-secretase followed by processive proteolysis by the PSEN-containing γ-secretase complex. Trimming of initially formed long Aβ by γ-secretase leads to release of Aβ40 and Aβ42. Aβ production in the late endosomal/lysosomal compartment is augmented by FAD mutations in PSEN1 or PSEN2, resulting in intracellular accumulation of the potentially pathogenic Aβ42 peptide. In contrast, cleavage of APP at the cell surface results in relatively lower levels of Aβ42, which is released from the cell together with Aβ40. Cell 2016 166, 13-15DOI: (10.1016/j.cell.2016.06.034) Copyright © 2016 Elsevier Inc. Terms and Conditions