Animal Models of Frontotemporal Dementia

Frontotemporal dementia (FTD) is a multifaceted syndrome with a high degree of clinical and �neuropathological variability, an extensive genetic contribution, and involvement of multiple proteins. FTD accounts for up to 50% of dementias with the onset prior to age 60. The heterogeneous genetic, clinical, and pathological manifestations of FTD have created challenges in generating clinically relevant animal models with which to test new therapeutic approaches. Nevertheless, tau transgenic models have been developed in mice, Drosophila melanogaster , and Caenorhabditis elegans in the past decade. These models have played an important role in elucidating a number of mechanisms associated with tau FTD-related neurodegeneration, and it is likely that these preclinical models will help to facilitate new therapeutic strategies. It is clear that both wild-type and mutated tau protein are sufficient to elicit tauopathy, although mutated tau increases the severity of the pathology. Furthermore, the aberrant expression and/or incorrect temporal/developmental expression of tau may also cause tau pathology. Importantly, these tau models have clarified some long-held theories pertaining to tau and neurodegeneration. For example, it has been shown that oxidative stress plays a crucial role in FTD and that tau pathology reactivates the cell cycle machinery. Conversely, tau aggregates are not necessary for tau neurotoxicity. However, new models representing other forms of FTD need to be developed and much work still remains before the disease is clearly understood and disease-modifying therapies become available.