Figure 6. Schematic representation of the potential role of C99 in the regulation of cholesterol trafficking, and its relevance to AD.

By means of its affinity for cholesterol, uncleaved C99 at the ER induces the uptake and retrograde transport of cholesterol from the PM to the ER, resulting in the formation of a lipid raft domain, or MAM. These C99‐dependent lipid rafts passively segregate and organize lipid‐binding proteins, thereby facilitating their interaction and the regulation of specific signaling pathways. Failure to cleave C99 completely would result in a futile cycle of continuous uptake of extracellular cholesterol and its mobilization from the PM to the ER, resulting in the upregulation of MAM formation and activation, which in turn would cause the upregulation of SMases, ACAT activity, and LD deposition. Closing the cycle, this accumulation of cholesterol in membranes also induces APP internalization and its interaction and cleavage by BACE1, and the downregulation of α‐secretase activity.