Figure 1

Typical trafficking route of APP, BACE1, α-secretase and γ-secretase. Newly synthesized APP, BACE1, α-secretase and γ-secretase traffic through the secretory pathway, from the ER to Golgi/TGN and to the plasma membrane, during which process retrieval may occur and APP may be cleaved to generate Aβ. At the plasma membrane APP is largely subjected to non-amyloidogenic processing by α-secretase to release sAPPα. Un-cleaved APP and various secretases at the plasma membrane may undergo endocytosis via early endosome to late endosome/lysosome for degradation. Acidic endosome/lysosome provides optimal environment for BACE1 activity and APP is mainly subjected to amyloidogenic processing for Aβ production in these compartments. In addition, a fraction of these proteins in endosome can be either recycled back to plasma membrane or retrieved back to TGN.