Decreased insulin-receptor signaling promotes the autophagic degradation of β-amyloid peptide in C-elegans

Autophagy is a conserved membrane trafficking pathway that mediates the delivery of cytoplasmic substrates to the lysosome for degradation. Impaired autophagic function is implicated in the pathology of various neurodegenerative diseases. We have generated transgenic C. elegans that express human (beta-amyloid peptide (A beta) in order to examine the mechanisms) of A beta-toxicity. In this model, A beta expression causes autophagosome accumulation, thereby mimicking a pathology found in brains of Alzheimer's disease patients. Furthermore, we demonstrate that decreased insulin-receptor signaling [using the daf-2(e 1370) mutation] suppresses A beta-induced paralysis by a mechanism that requires autophagy. Surprisingly, the daf-2 mutation also decreases A beta-induced autophagosome accumulation. These observations can be explained by a model in which decreased insulin-receptor signaling promotes the maturation of autophagosomes into degradative autolysosomes, whereas A beta impairs this process. Consistent with this model, we find that RNAi-mediated knock-down of lysosomal components results in enhanced A beta-toxicity and autophagosome accumulation. Also, A beta; daf-2(e 1370) nematodes contain more lysosomes than either A beta or control strains. Finally, we demonstrate that decreased insulin-receptor signaling promotes the autophagic degradation of A beta.