Toxicities of amyloid-beta and tau protein are reciprocally enhanced in the Drosophila model.

ABSTRACT

Extracellular aggregation of amyloid-beta (Aß) and intracellular tau tangles are two major pathogenic hallmarks and critical factors of Alzheimer's disease. A linear interaction between Aß and tau protein has been characterized in several models. Aß induces tau hyperphosphorylation through a complex mechanism; however, the master regulators involved in this linear process are still unclear. In our study with Drosophila melanogaster, we found that Aß regulated tau hyperphosphorylation and toxicity by activating c-Jun N-terminal kinase. Importantly, Aß toxicity was dependent on tau hyperphosphorylation, and flies with hypophosphorylated tau were insulated against Aß-induced toxicity. Strikingly, tau accumulation reciprocally interfered with Aß degradation and correlated with the reduction in mRNA expression of genes encoding Aß-degrading enzymes, including dNep1, dNep3, dMmp2, dNep4, and dIDE. Our results indicate that Aß and tau protein work synergistically to further accelerate Alzheimer's disease progression and may be considered as a combined target for future development of Alzheimer's disease therapeutics.