Figure 10.

Schema illustrating our proposed model by which high cholesterol levels regulate Aβ-induced autophagy. In mitochondria (A), cholesterol-enrichment enhances ROS generation triggered by Aβ. The increased oxidative stress inhibits the delipidation activity of ATG4B on LC3B, and therefore, favors autophagosome synthesis. ER-mitochondria contact sites contribute to the biogenesis of these vesicles, which mainly enclose Aβ aggregates together with other more soluble forms of the peptide. In contrast, the accumulation of cholesterol in lysosomes (B) affects the levels and distribution of RAB7A and SNARE proteins, which ultimately impairs the ability of lysosomes to fuse with autophagosomes and/or amphisomes. Inhibition of the autophagy flux by high cholesterol levels reduces MAPT and Aβ clearance and stimulates Aβ secretion. DRMs, detergent-resistant membranes; mGSH, mitochondrial glutathione; LE, late endosome; MVB, multivesicular body; ROS, reactive oxygen species.