Relative expression of 3R and 4R tau isoforms in Alzheimer's disease and argyrophilic grain disease brains

Abstract

Aggregation of microtubule-binding protein tau abnormally hyperphosphorylated in certain populations of neurons and glial cells is a pathological hallmark of several neurodegenerative disorders. Alternative splicing of exon 10 of tau gives rise to isoforms with 3 or 4 tandem repeats in the microtubule binding domain, which are named respectively 3R and 4R tau. The dysregulation of 3R and 4R tau expression is a pathogenic feature of certain disorders with tau pathology. For example, 3R tau forms predominate in Pick's disease, 4R tau forms in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia with parkinsonims and in argyrophilic grain disease (AGD), whereas both 3R and 4R isoforms of the protein 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.