Overexpression of four-repeat tau mRNA isoforms in progressive supranuclear palsy but not in Alzheimer's disease

Perturbations in the microtubule-associated protein tau occur in several hu man neurodegenerative diseases. In Alzheimer's disease and progressive supr anuclear palsy (PSP), tau proteins assemble into straight and paired helica l filaments that form intraneuronal deposits of neurofibrillary tangles (NF Ts), The mechanisms underlying the aberrant assembly of tau into NFTs is un known. To determine whether alterations in the expression of the carboxyl-t erminal variants of tau contribute to NFT formation, we analyzed tan mRNA i soform expression in select regions of control, Alzheimer's disease, and PS P brains. In Alzheimer's disease, there were no alterations in tau mRNA iso form expression, However, in PSP, the levels of tau mRNA isoforms containin g four microtubule binding domains were increased in the brainstem but not the frontal cortex or cerebellum. The brainstem in PSP has extensive NFT pa thology, whereas the frontal cortex and cerebellum are relatively spared, s uggesting that alterations in tau mRNA isoform expression occur in NFT-vuln erable regions in this disease. An increase in the four-repeat tau mRNA may lead to an increase in four-repeat tall protein isoforms and may contribut e to the formation of NFTs in PSP. A similar increase in four-repeat tau mR NA has been reported for mutations associated with frontotemporal dementia and parkinsonism linked to chromosome 17.