Distinct functions of tau isoforms in Alzheimer's disease

摘要

Tau, a class of low molecular mass microtubule-associated proteins mat is also involved in paired helical filament formation in Alzheimer's disease (AD) brains and in other cellular inclusion lesions in neurodegeneration diseases with dementia such as tauopachies. Although tau proved to be the causal molecule for FTDP-17, tau was examined by many studies. Here, the two representative missense mutations (Val337Met and Asn279Lys; amino acid number was referred according to tau_(1-441) nomenclature) and intronic mutation (+16 in intron 10) were chosen to examine the effects of irontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17)-associated tau mutations on isoform expression, microtubules or the cell shape. The latter was particularly interesting because it is the mutation type to explain the most frequent FTDP-17 cases where tau isoforms with three and four microtubule-binding repeat domains (referred to as 3R-tau and 4R-tau, respectively) were expressed in an unbalanced ratio. To see an isoform-specific distinct function, we studied cellular distribution of tau isoforms by proving tau with EGFP and found a specific function of each tau isoform in neuronal processes.