Transgenic Mouse Models of Tauopathy in Drug Discovery

W.      Noble; D.P.      Hanger; J.-M.      Gallo

Abstract

Tauopathies, including Alzheimers disease, are neurodegenerative diseases characterized by the deposition of hyperphosphorylated tau protein in the central nervous system, and are the major cause of dementia in later life. Considerable advances have been made in developing mouse models that recapitulate, to varying extents, the development of human tau pathology, and the learning and memory deficits characteristic of some tauopathies. Furthermore, such models have been used to show promising disease-modifying effects in pre-clinical testing of new therapeutics. Various strategies have been utilised to generate mouse models of tauopathies. Some of the most enlightening models developed to date either constitutively or inducibly express pathogenic tau mutations. These animals have been instrumental in defining critical disease-related mechanisms, including the observation that tangles are not the toxic form of tau in disease. Here, we discuss the strengths and weaknesses of well characterised transgenic models that emulate human tauopathy, and include a comprehensive listing of the main phenotypic characteristics of all reported tau transgenic rodents. We summarise the use of tau mice for the development and evaluation of new therapeutic approaches, and their utility in identifying novel drug targets. In addition, we review the parameters to be considered in the development of the next generation of rodent models of tauopathy, aimed at further increasing our understanding of disease aetiology and in evaluating novel treatments.

Keywords: Tauopathy, neurofibrillary tangle, kinase, transgenic model, therapeutic, phosphorylation, phenotype, microtubule-associated protein tau, neurodegeneration, Alzheimer's disease