A range of different in vivo model systems is now available that can be used to investigate both the development and progression of tauopathies (see Table 2 for future directions). These models mimic many of the basic cellular changes that accompany development of tauopathy. Additionally, some of the models share clinical features and distribution of tau pathology that could be compared to human 4R tauopathies such as progressive supranuclear palsy (PSP). PSP is a rare parkinsonian movement disorder that is associated with early postural instability and supranuclear vertical gaze palsy (47). The brains of PSP patients display neurofibrillary tangles that are primarily localized to the basal ganglia, diencephalon, and the brainstem (48,49). Brainstem regions that are usually affected in PSP included the locus ceruleus, pontine nuclei, and pontine tegmentum. Additionally, the cerebellar dentate nuclei and spinal cord are frequently affected in PSP patients (48,49). The distribution of the neurofibrillary tau pathology in the JNPL3 mice overlaps many of the same regions affected in PSP, including the pontine nucleus, the dentate nucleus, and the spinal cord. 0N4R P301S mice (41) also showed a similar distribution of pathology. Additionally, the reduced vocalization and progressive
movement disorder, including rigidity, observed in the JNPL3 model is similar to that observed in PSP patients. In addition, the selective distribution of 4R tau in both neurons and glia is a feature observed in both PSP and these mouse models.
The neuronal response to tauopathy, including of gene expression and protein (level and modification) changes, can now be investigated at various pathological stages in these models and compared with observations from end-stage human tissue. Additionally, multiple disease modifiers may now be identified in the more simple systems such as in the fly or worm, which may lead to a greater understanding of the mechanisms that result in tau-induced neurodegeneration and perhaps identify additional therapeutic targets. It is important however to recognize the limitations of these simple "genetic" animal models and follow-up studies in mouse models will be required to verify the relevance of the findings in these systems.
The development of multiple animal models of tauopathy has also enabled the field to investigate the relationship between tau dysfunction and other proteins previously implicated in neurodegenerative disease including Ap, a-synuclein, and various tau kinases/phosphatases. Given the similarities between the various protein aggregation disorders, these interactions may provide essential clues for understanding the basic process of tau-associated neurodegeneration and for developing therapeutic strategies (Fig. 2).
Comparisons of various tau transgenic mice on different mouse strain backgrounds should further our understanding of how genetic or environmental factors modify the progression of tauopathy. Novel inducible models of tauopathy should also help determine which aspects of the disease process are reversible and which stages are associated with functional deficits. Overall the rapid development of animal models of tauopathy in the last 4 yr will inevitably accelerate progress in understanding the pathogenesis of tauopathy and should also identify potential therapeutic approaches that can be used to treat these diseases in human patients.
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