In addition to the range of mouse models now available, there have been attempts to use nonmammalian systems to model the tau dysfunction observed in human tauopathies. Although often ignored by many mouse-based researchers, these systems have proven useful in modeling some aspects of the disease while providing relatively simple screening systems for potential therapeutics before trials in mammals.
One such system is a lamprey model for tau dysfunction developed by Hall and colleagues (42). By expressing wild-type human tau in the large anterior bulbar cells (ABCs) of the lamprey, Hall et al. (42) succeeded in producing a fish model of tau dysfunction. Tau within these ABCs became hyperphosphorylated and filamentous, and the neurons degenerated, resulting in a lamprey tauopathy that can be staged similarly to human tauopathies. The ease of therapeutic trials using this lamprey system allows the model to be a valuable link between cellular models and the in vivo mammalian models detailed earlier. Hall et al. (43) has recently utilized this system to screen a novel proprietary compound aimed at blocking tau filament formation. Limitations of this model system include differences of central nervous system and the inability to perform cognitive and motor tests that accompany the tauopathies that occur in complex organisms.
Kraemer et al. recently generated a Caenorhabditis elegans model of tau pathology (44). Expression of tau with either the P301L or V377M mutation resulted in worms with locomotor deficits, accumulation of insoluble tau protein, and increased tau phosphorylation. Axonal degeneration and neuronal loss were also reported in this mold. The simplicity of this model makes it an attractive system with which to screen potential therapeutic compounds before trials in mammals.
A Drosophila model of tauopathy expressing the human tau containing the R406W mutation also mimicked many aspects of tauopathy without the development of NFTs (45). Aged flies showed progressive neurodegeneration, accumulation of abnormally phosphorylated tau, but lacked the large neurofibrillary accumulations of tau that characterize human tauopathies. This model system suggested that mature tau pathology may not be necessary to result in the neurodegenerative process. Additionally, this model has now been used to examine the gene expression changes that occur as the result of tau-related neurodegeneration (46). Evidence of these expression changes such as those in lysosomal and cellular stress response genes in the Drosophila model will now allow us to more closely investigate similar changes in both mouse models and human tauopathies.
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