Quantitative analysis of 3R and 4R tau isoform expression in Alzheimer's disease and argyrophilic grain disease

Abstract

Alternative splicing of exon 10 of microtubule-associated protein tau gives rise to isoforms with 3 or 4 repeats in the microtubule binding domain. In the group of neurodegenerative diseases called tauopathies these isoforms of tau, named respectively 3R and 4R tau, are hyperphosphorylated and accumulate in neurons and glia in a disease-specific manner. Thus, 3R tau forms predominate in Pick's disease, 4R tau forms in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and in argyrophilic grain disease (AGD), whereas both 3R and 4R isoforms are present in Alzheimer's disease (AD). It has also been shown that the ratio 4R/3R tau mRNA is increased in some brain regions in PSP and CBD, whereas in AD and Pick's disease this ratio is not different from controls. In order to determine whether alterations in the expression of 4R versus 3R tau mRNA might contribute to the accumulation of 4R tau into argyrophilic grains in AGD, we have examined brain samples from AGD patients in comparison to control cases and early stages of AD (Braak III-IV) by quantitative RT-PCR using variant-specific 3R and 4R primers and probes. In the regions analyzed, which include the anterior and posterior hippocampus, frontal cortex and temporal cortex, we have not found significant differences in the ratio 4R/3R between AGD, early AD and controls. These results are in agreement with previous studies on AD. The lack of alterations in the expression of 3R and 4R tau mRNA suggests that post-translational events are the main factors controlling the composition of tau isoforms that aggregate in neurofibrillary tangles in AD and in argyrophilic grains in AGD.