Mapping pathogenic processes contributing to neurodegeneration in Drosophila models of Alzheimer’s disease Liza Bergkvist 1† , Zhen Du 2,3 , Greta Elovsson 1 , Hanna Appelqvist 1,4 , Laura S. Itzhaki 3 , Janet R. Kumita 2 , Katarina K  agedal 4 and Ann-Christin Brorsson 1 1 Division of Molecular Biotechnology, Department of Physics, Chemistry and Biology, Link€ oping University, Sweden 2 Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, UK 3 Department of Pharmacology, University of Cambridge, UK 4 Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Link€ oping University, Sweden Keywords Alzheimer’s disease; amyloid-b; Drosophila melanogaster; endo-lysosomal system; neurodegeneration Correspondence A.-C. Brorsson, Division of Molecular Biotechnology, Department of Physics, Chemistry and Biology, Link€ oping University, Link€ oping 58183, Sweden. E-mail: anki@ifm.liu.se † Present address Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI, USA (Received 26 August 2019, revised 21 November 2019, accepted 9 December 2019) doi:10.1002/2211-5463.12773 Alzheimer’s disease (AD) is the most common form of dementia, affecting millions of people and currently lacking available disease-modifying treat- ments. Appropriate disease models are necessary to investigate disease mechanisms and potential treatments. Drosophila melanogaster models of AD include the Ab fly model and the AbPP-BACE1 fly model. In the Ab fly model, the Ab peptide is fused to a secretion sequence and directly overexpressed. In the AbPP-BACE1 model, human AbPP and human BACE1 are expressed in the fly, resulting in in vivo production of Ab pep- tides and other AbPP 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 Ab fly model, this correlates with high Ab 1–42 levels and down-regulation of the levels of mRNA encod- ing lysosomal-associated membrane protein 1, lamp1 (a lysosomal marker), while in the AbPP-BACE1 fly model, neuronal cell death correlates with low Ab 1–42 levels, up-regulation of lamp1 mRNA levels and increased levels of C-terminal fragments. In addition, a significant amount of AbPP/Ab antibody (4G8)-positive species, located close to the endosomal marker rab5, was detected in the AbPP-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 patho- genesis or screening for potential treatments. Alzheimer’s disease (AD) is a neurodegenerative disor- der that leads to progressive cognitive decline. It is the most prevalent form of dementia, affecting 11% of the population over the age of 65, and it is the sixth leading cause of death in the United States [1].A hallmark of the disease is the aggregation of the amy- loid b (Ab) peptide into fibrillar deposits known as amyloid plaques [2]. However, research in the AD field Abbreviations AD, Alzheimer’s disease; Ab, amyloid beta; AbPP, amyloid beta precursor protein; BACE1, beta-site AbPP-cleaving enzyme; CTFs, C- terminal fragments; MCI, mild cognitive impairment; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labelling. 338 FEBS Open Bio 10 (2020) 338–350 ª 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.