Transgenic zebrafish model of neurodegeneration.

In Alzheimer's disease (AD), the microtubule-associated protein, tau, is compromised in its normal association with microtubules and forms into paired helical filaments (PHF) that are the hallmark cytoskeletal pathology of the disease. Several posttranslational modifications of tau including phosphorylation have been implicated in AD pathogenesis. In addition, and importantly, mutations in the genes encoding human tau have recently been implicated in a variety of hereditary dementias, collectively termed frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). This has rekindled interest in the importance of tau in neurodegenerative diseases (cf. Vogel [1998] Science 280:1524-1525; Goedert et al. [1998] Neuron 21:955-958; D'Souza et al. [1999] PNAS 96:5598-5603). Despite significant progress in the field of tau biology and neurodegenerative diseases, several important issues remain unresolved. The early functional consequences of tau alterations in living neurons is incompletely understood, and it is not clear how tau in neurodegenerative diseases becomes redistributed from its normal concentration in neuronal axons to pathological inclusions in neuronal soma known as neurofibrillary tangles (NFT). One of the reasons for these gaps in knowledge is the relative paucity of model systems to study these processes. We have developed a transgenic model system to study the functional consequences and trafficking patterns in zebrafish neurons of human tau either mutated on sites associated with hereditary dementias or altered at select posttranslational modification sites. The overall guiding hypothesis is that the model allows dissection of a hierarchy of events relevant to potential mechanisms of neurodegenerative diseases related to critical early stages in development of disease. We showed that a FTDP-17 mutant form of human tau expressed in zebrafish neurons produced a cytoskeletal disruption that closely resembled the NFT in human disease. This model system will prove useful in the study of other mutant taus in vertebrate neurons in vivo, and the approaches developed here will have broad usefulness in the study of functional consequences and potential genetic analyses of introducing into living vertebrate neurons other molecules involved in the pathogenesis of neurodegenerative diseases.