Mapping pathogenic processes contributing to neurodegeneration in Drosophila models of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people and currently lacking available disease‐modifying treatments. Appropriate disease models are necessary to investigate disease mechanisms and potential treatments. Drosophila melanogaster models of AD include the Aβ fly model and the AβPP‐BACE1 fly model. In the Aβ fly model, the Aβ peptide is fused to a secretion sequence and directly overexpressed. In the AβPP‐BACE1 model, human AβPP and human BACE1 are expressed in the fly, resulting in in vivo production of Aβ peptides and other AβPP cleavage products. Although these two models have been used for almost two decades, the underlying mechanisms resulting in neurodegeneration are not yet clearly understood. In this study, we have characterized toxic mechanisms in these two AD fly models. We detected neuronal cell death and increased protein carbonylation (indicative of oxidative stress) in both AD fly models. In the Aβ fly model, this correlates with high Aβ(1–42) levels and down‐regulation of the levels of mRNA encoding lysosomal‐associated membrane protein 1, lamp1 (a lysosomal marker), while in the AβPP‐BACE1 fly model, neuronal cell death correlates with low Aβ(1–42) levels, up‐regulation of lamp1 mRNA levels and increased levels of C‐terminal fragments. In addition, a significant amount of AβPP/Aβ antibody (4G8)‐positive species, located close to the endosomal marker rab5, was detected in the AβPP‐BACE1 model. Taken together, this study highlights the similarities and differences in the toxic mechanisms which result in neuronal death in two different AD fly models. Such information is important to consider when utilizing these models to study AD pathogenesis or screening for potential treatments.