An evaluation of Drosophila as a model system for studying tauopathies such as Alzheimer’s disease

Abstract

Work spanning almost two decades using the fruit fly, Drosophila melanogaster, to study tau-mediated neurodegeneration has provided valuable and novel insights into the causes and mechanisms of tau-mediated toxicity and dysfunction in tauopathies such as Alzheimer's Disease (AD). The fly has proven to be an excellent model for human diseases because of its cost efficiency, and the availability of powerful genetic tools for use in a comparatively less-complicated, but evolutionarily conserved, in vivo system. In this review, we provide a critical evaluation of the insights provided by fly models, highlighting both the advantages and limitations of the system. The fly has contributed to a greater understanding of the causes of tau abnormalities, the role of these abnormalities in mediating toxicity and/or dysfunction, and the nature of causative species mediating tautoxicity. However, it is not possible to perfectly model all aspects of human degenerative diseases. What sets the fly apart from other animal models is its genetic tractability, which makes it highly amenable to overcoming experimental limitations. The explosion of genetic technology since the first fly disease models were established has translated into fly lines that allow for greater temporal control in restricting tau expression to single neuron types, and lines that can label and monitor the function of subcellular structures and components; thus, fly models offer an unprecedented view of the neurodegenerative process. Emerging genetic technology means that the fly provides an ever-evolving experimental platform for studying disease.

UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation

“…Drosophila melanogaster has emerged as an important model system for investigating the pathology of tauopathies at the cellular and molecular levels. Drosophila tauopathy AD models exhibit visible phenotypes such as brain vacuole formation, neuromuscular junction defects, larval and adult locomotor defects, impairment of learning and memory, and reduced lifespan 5 , 6 . Ectopic expression of human tau in Drosophila eyes induces a rough eye phenotype, which is widely used to screen for modifiers of Tau pathology 7 .…”

Age dependent trans-cellular propagation of human tau aggregates in Drosophila disease models

“…Hence, to gain a better perspective of the mechanism of tau propagation and its role in disease pathology, we developed a novel Drosophila in-vivo tauopathy model. Drosophila disease models have been widely accepted as they recapitulate many structural and functional aspects of human disease pathology and offer innumerable advantages over other model systems [12]. In our study, using the Drosophila in-vivo model, we demonstrate that human tau propagates trans-cellularly from the site of targeted expression to the additional regions of the adult fly brain by the factor of age.…”

“…We tested if these pathogenic tau aggregates possess the similar tendency of trans-cellular migration in Drosophila as they are reported in the higher organisms and in in-vitro studies as stated above. Fly disease models offer innumerable advantages over other model systems such as rapid disease onset, easy phenotypic scoring in bulk, ease to study the status of nervous system, and to elucidate the effect of molecules and genetic modifiers on disease pathogenesis and phenotypic manifestation [12].…”

In vivo Evaluation of a Newly Synthesized Acetylcholinesterase Inhibitor in a Transgenic Drosophila Model of Alzheimer’s Disease

“…Drosophila melanogaster offers several advantages as a model organism, such as a well-defined genome, the possibility to study hundreds of animals simultaneously, and low cost of maintenance ( Sivanantharajah et al, 2019 ; Tue et al, 2020 ). Moreover, the easily accessible Drosophila brain allows one to image and quantify amyloid plaque deposition in amyloid transgenic models, along with the possibility to investigate selected areas of the brain involved in cognitive processes, such as the mushroom bodies ( Hwang et al, 2019 ; Zhong et al, 2019 ).…”