Favorably against the odds - autophagy control despite advanced amyloid- ß toxicity.

Alzheimer disease (AD) is a devastating condition associated with loss of proteostasis control and autophagy failure, leading to progressive neuronal cell death. However, the relationship between the activity in macroautophagy (MA) and chaperone-mediated autophagy (CMA) in the context of cargo clearance remains poorly dissected. We have found that cell death is observed as early as 24 h into amyloid-induced toxicity, despite enhanced and fully functional autophagy activity even at late stages of injury progression, whereas inhibition of autophagosome degradation indeed shifts apoptosis onset to an earlier point in time. A prolonged intermittent fasting (IF) regimen during severe paraquat-induced neuronal injury enhances both MA- and CMA-associated protein clearance in the brain differentially and region-specifically. These results have a number of practical implications that point towards a major focus to decrease proteinaceous cargo burden, while enhancing autophagy flux early and late in the pathogenesis, so as to rapidly offset the disequilibrium between cargo and machinery flux. In this punctum, we summarize these findings.