Diversity of Abeta aggregates produced in a gut-based Drosophila model of Alzheimer's disease

Abstract

Alzheimers disease (AD) is a neurodegenerative disease manifested by memory loss and premature death. One major histopathological hallmark of AD is the amyloid plaques formed by aggregates of the amyloid-beta (Abeta) peptide and the Abeta aggregation process results in amyloid fibrils with different structures. Herein, we investigate the heterogeneity of Abeta aggregates produced by Drosophila melanogaster expressing the Abeta1-42 peptide with the Arctic mutation E22G (Arctic flies) or a dimeric construct of Abeta1-42 (T22Abeta1-42 flies) in the digestive tract. Staining of the gut of the flies using luminescent conjugated oligothiophenes (LCOs) revealed that the amount of Abeta aggregates increased in both genotypes with age. The LCOs also exhibited distinct staining patterns in the flies. The expression of T22Abeta1-42 resulted in a heavier Abeta load compared to Abeta1-42 with the Arctic mutation. Since the genotypes have similar median survival times, the result indicates that the toxicity of the combined number of aggregates in the Arctic flies is higher compared to the T22Abeta1-42 flies. Stability measurements showed that the most accumulated Abeta species in the Arctic and the T22Abeta1-42 flies were found in the 4 M and 5 M Gua-HCl-fraction, respectively. This indicates that prefibrillar Abeta aggregates constitute the toxic species in Arctic flies while the cause of death in T22Abeta1-42 flies might be the massive load of insoluble aggregates. The study shows that even though the different Abeta peptides resulted in an equal reduction of the lifespan, they formed an array of different aggregates confirming the heterogeneity of this process. Overall, our findings support that distinct Abeta aggregates can exhibit different pathological effects, and we foresee that our Drosophila models can potentially aid in identifying anti-Abeta agents targeting different types of aggregated Abeta species.