FIGURE 9.

The Catabolism of APP-CTFs is independent of macroautophagy but dependent on lysosomal flux. Following its partial proteolysis at or close to the plasma membrane, a significant amount of APP-CTFs are delivered to lysosomes for degradation. Under conditions of efficient lysosomal flux, the generation of nascent autophagosomes did not directly alter the expression of full-length APP, APP-CTFs, or the secretion of Aβ, thus indicating that autophagy does not directly influence APP metabolism. However, APP-CTFs and Aβ accumulated under conditions where either primary (Sandhoff and GM1 gangliosidosis) or secondary (NPC1) lysosomal flux was impaired. Considering autophagic and endocytic cargo converge at the lysosome, efficient lysosomal flux is essential for degrading cargo from both routes. Note: the lysosome depicted here represents an active lysosome receiving cargo from autophagic and endocytic routes. LC3-II is present on autolysosomal but not lysosomal membranes.