Title : Neuroprotective effects of pan-neuronal Hsp104 co-expression in suppressing amyloid-? aggregation and toxicity
Abstract:
Alzheimer’s disease (AD) is driven by the accumulation of toxic amyloid-β aggregates in the brain. AD is the 6th leading cause of death among adults aged 65 and older, yet effective treatments for the disease remain scarse. This study evaluates whether the yeast-derived protein disaggregase Hsp104 (Heat-shock protein 104) can mitigate amyloid-β-induced neurotoxicity, specifically with amyloid-β42 (Aβ42) in vivo using Drosophila melanogaster as a genetic model. It hypothesizes that pan-neuronal expression of Hsp104 would mitigate the behavioral decline in terms of locomotion and sleep patterns in Drosophila where the gene producing Aβ42 aggregates is active.
AlphaFold was used to predict structural interactions between Hsp104 and Aβ42. An independent dual binary GAL4/UAS and QF/QUAS expression system incorporating elav-GAL4 and nSyb-QF drivers was used to generate Drosophila melanogaster with pan-neuronal co-expression of human Aβ42 and yeast Hsp104. Behavioral and survival outcomes were assessed using longitudinal negative geotaxis assays, Kaplan–Meier survival analysis, and TriKinetics Drosophila Activity Monitoring (DAM) to evaluate locomotor function, sleep-wake cycle, and circadian rhythmicity. Pan-neuronal Hsp104 co-expression significantly improved climbing performance compared with Aβ42-only flies with performance approaching that of wild-type and Hsp104-only controls throughout the 40-day study period. Survival analysis demonstrated significantly improved survival relative to Aβ42-only flies corresponding to an estimated 95% reduction in mortality risk.
These findings suggest that pan-neuronal Hsp104 expression does rescue Aβ42-induced phenotypes, substantially improving locomotor function and survival while failing to restore normal sleep architecture. Persistence of sleep deficits despite improvement in other behavioral measures suggests circuit-specific differences in vulnerability to Aβ42 toxicity. Further studies incorporating additional genetic controls and expanded behavioral analyses will further validate these findings and define the therapeutic potential of Hsp104.
