Differential effects of amyloid-β and tau on UCH gene expression in Drosophila models of Alzheimer's disease.

Background

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive impairments in learning and memory. Substantial evidence indicates that dysfunction of the ubiquitin-proteasome system (UPS) in the AD brain leads to aberrant protein aggregation, ultimately resulting in synaptic dysfunction and neuronal loss. In this study, we investigated the effects of pan-neuronal expression of TauWT or Aβ42-key pathological hallmarks of AD-on the expression of UCH, a critical UPS component, in Drosophila melanogaster at three time points: 5, 15, and 25 days after eclosion.

Methods

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Results

UCH mRNA levels were quantified using real-time RT-PCR. UCH expression showed an age-dependent downregulation in Aβ42 transgenic flies over all three post-eclosion intervals. While UCH transcription witnessed no significant change in 5-day-old TauWT transgenic flies, there was a considerable decline in UCH mRNA levels in 15- and 25-day-old flies. Notably, Aβ42 had a more prominent impact on UCH gene expression than TauWT across all three time points.

Conclusion

TauWT and Aβ42 exert independent adverse effects on UCH expression. An apparent age-related trend was observed in the fly models, whereby Aβ42 showed a relatively stronger influence on UCH transcription compared with TauWT. Accordingly, therapeutic strategies that target both Tau and amyloid-β may warrant consideration.