Novel Tau-mediated Neurodegeneration Mechanisms

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The experiments performed during the first funded period of this project (2000-2004) led to the first evidence of a direct link between senile plaques and tau pathology in an Alzheimer’s disease (AD) cell model system (Rapoport et al., 2002). This study showed that neurons expressing human tau degenerated in the presence of preaggregated beta amyloid (Aβ), while no signs of degeneration were detected in Aβ-treated tau-depleted neurons (Rapoport et al., 2002). Data obtained during the second funded period (2005-2009) have identified calpain-mediated tau cleavage leading to the generation of a 17 kDa fragment as an important step in neuronal degeneration (Park and Ferreira 2005, Park et al., 2007). More recently, we have obtained preliminary evidence suggesting that the levels of this tau neurotoxic fragment might be elevated not only in AD but also in other tauopathies. However, the mechanisms by which this tau fragment could induce neurotoxicity remain poorly understood. We speculate that the generation of a 17 kDa tau fragment is a conserved mechanism leading to neuronal degeneration in different tauopathies. To test this hypothesis, we will determine: 1) the presence of the 17 kDa tau fragment in brain samples obtained from AD and other tauopathies patients; and 2) we will generate a transgenic animal model in which this toxic fragment is over expressed. This animal model could provide an essential tool for future studies on the neurotoxic effects of this fragment in central neurons that develop in situ. These experiments will be performed by means of a combination of techniques including: Western blot analysis, immunocytochemistry, calpain activity assays, real-time RT-PCR, and homologous recombination techniques. The data obtained could provide useful for the diagnosis, prevention, and eventually the treatment of AD and other tauopathies.