FIGURE 8.

Molecular mechanisms controlling GSK-3, lysosomes, mTOR, and Aβ burdens in the 5XFAD brain. In brains of untreated mice, GSK-3 is activated by Aβ peptides. Hyperactive GSK-3 and mutant PS1 impair lysosomal acidification. This, in turn, accelerates accumulation of Aβ burdens. GSK-3 activates mTOR, but mTOR is also inhibited by the disruption in lysosome activity and by accumulated APP/Aβ burdens. The “net” effect on mTOR activity is inhibition. In L803-mts-treated mice, inhibition of GSK-3 restores lysosomal acidification and in addition prevents the deleterious effect of mutant PS1 on lysosomal acidification (by yet unknown mechanism). The normalization in lysosomal activity results in reduced Aβ burdens. Lowering of Aβ burdens and restoring lysosomal activity enable reactivation of mTOR, which inhibits autophagy. Minus signs mark inhibition, plus signs mark activation, and dashed arrows indicate processes reported in the literature.