Investigation of mechanism of tauopathy and application for clinical diagnosis

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1)We have made an antibody which selectively recognized the four-repeat tau protein. (4R-tau). Using this antibody, we examined the brain tissue of the patients with progressive supranuclear palsy (PSP) and demonstrated that tau-positive tufted astrocyte, pretangle and theads were composed of 4R-tau and 4R-tau-positive tufted astrocytes were not reactive for anti-GFAP antibody.2)Using the antibody for 4R-tau, we are establishing the method for measure of 4R-tau in cerebrospinal fluid. The method is based on ELISA.3)We have found a new mutation of the tau gene (L266V) in a familial tauopathy (frontotemporal dementia and parkinsonism linked to chromosome 17) and we examined the brain of a patient of this kindred and demonstrated Pick body-like inclusions and unique tau-positive astrocytes.4)We have reported two patients of the two families with P301L tau mutation, who showed different phenotype. Their genotypes of the tau gene were different at three sites, and the studies suggested they do not share a common founder for P301L mutation and either of the two less prevalent genotypes observed in patient 2 may be the factor to modify the phenotype of P301L mutation into those unusual clinical features with prominent parkinsonism.5)Using quantitative RT-PCR method, we investigated the expression level of tau mRNA isoforms in the frontal cortex and globus pallidus of patients with PSP and corticobasal degeneration (CBD). The 4R/3R ratios in frontal cortices of CBD and globus pallidus of PSP and CBD were significantly higher than the control. There was no correlation between the expression patterns of tau mRNA isoforms and p-tau accumulation. Our findings suggest that neurodegeneration of PSP and CBD could be regulated by alternative splicing of tau mRNA to yield high 4R/3R ratio but also other factors such as post-transcriptional or translational modifications may play a role in the pathogenesis of specific neurodegeneration in PSP and CBD.