Decreased Insulin-Receptor Signaling Promotes the Autophagic Degradation of β-Amyloid Peptide inC. elegans

Abstract

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 β-amyloid peptide (Aβ) in order to examine the mechanism(s) of Aβ-toxicity. In this model, Aβ 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(e1370) mutation] suppresses Aβ-induced paralysis by a mechanism that requires autophagy. Surprisingly, the daf-2 mutation also decreases Aβ-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 Aβ impairs this process. Consistent with this model, we find that RNAi-mediated knock-down of lysosomal components results in enhanced Aβ-toxicity and autophagosome accumulation. Also, Aβ; daf-2(e1370) nematodes contain more lysosomes than either Aβ or control strains. Finally, we demonstrate that decreased insulin-receptor signaling promotes the autophagic degradation of Aβ.

Starvation triggers Aβ42 generation from human umbilical vascular endothelial cells

“…Li et al found that macroautophagy was protective from normal aging while exerted harmful effect when Ab 42 was overexpressed [33,39,40]. In muscle cell, it was also shown that amyloid was degraded through macroautophagy pathway and suppressing it would lead to amyloid accumulation and toxicity [41][42][43]. Our data again demonstrated the dual role of macroautophagy in the amyloid processing in different types of cell and different condition.…”

Autophagy and ageing: Insights from invertebrate model organisms

“…Drosophila dynein mutants with impaired autophagosome-lysosome fusion display premature expanded Huntingtin aggregation Rubinsztein et al, 2005). In a C. elegans model for Alzheimer's disease, expressing the human ␤-amyloid peptide (A␤), inhibition of autophagy exacerbates A␤ toxicity, especially in genetic backgrounds deficient for insulin/IGF-1 signalling (Florez-McClure et al, 2007). Moreover, expression of human amyloid peptide 42 (A␤ 1-42 ), but not A␤ 1-40 , induces early onset and progressive neuropathology characterized by defective autophagic/lysosomal degradation (accumulation of dysfunctional autophagic vesicles) in the Drosophila brain (Ling and Salvaterra, 2011).…”

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…These results suggest the activation of an aggregation mechanism and have been substantiated in mice, in which a heterozygous mutation in the IGF-1 receptor is protective in a mouse model of AD 164 . Autophagic degradation of Ab is also required for the protective effect of reduced IIS in Ab 1-42 -expressing worms, whereas the role of proteasome activity has not been examined 168 . In mice, IIS effects could be independent of autophagy since IGF1R inhibition results in decreased autophagy 31 .…”