Thioredoxin-80 protects against amyloid-beta pathology through autophagic-lysosomal pathway regulation

Aggregation and accumulation of amyloid beta (Aβ) are believed to play a key role in the pathogenesis of Alzheimer's disease (AD). We previously reported that Thioredoxin-80 (Trx80), a truncated form of Thioredoxin-1, prevents the toxic effects of Aβ and inhibits its aggregation in vitro. Trx80 levels were found to be dramatically reduced both in the human brain and cerebrospinal fluid of AD patients. In this study, we investigated the effect of Trx80 expression using in vivo and in vitro models of Aβ pathology. We developed Drosophila melanogaster models overexpressing either human Trx80, human Aβ₄₂, or both Aβ₄₂/Trx80 in the central nervous system. We found that Trx80 expression prevents Aβ₄₂ accumulation in the brain and rescues the reduction in life span and locomotor impairments seen in Aβ₄₂ expressing flies. Also, we show that Trx80 induces autophagosome formation and reverses the inhibition of Atg4b-Atg8a/b autophagosome formation pathway caused by Aβ₄₂. These effects were also confirmed in human neuroblastoma cells. These results give insight into Trx80 function in vivo, suggesting its role in the autophagosome biogenesis and thus in Aβ₄₂ degradation. Our findings put Trx80 on the spotlight as an endogenous agent against Aβ₄₂-induced toxicity in the brain suggesting that strategies to enhance Trx80 levels in neurons could potentially be beneficial against AD pathology in humans.