Relationship of the extended tau haplotype to tau biochemistry and neuropathology in progressive supranuclear palsy

Abstract

Two extended haplotypes of the tau gene (H1 and H2) have been described. The frequency of H1 haplotype is increased in progressive supranuclear palsy (PSP). PSP is associated with filamentous tau lesions in neurons and glia, which are reportedly composed exclusively of tau isoforms with four repeats in the microtubule-binding domain (4R tau). To determine the influence of the tau haplotype on tau isoform composition and neuropathology, we studied 25 PSP cases and 6 Alzheimer's disease patients matched for age, sex, and postmortem delay. In the basal ganglia, tau and amyloid burdens were determined to see if there was an effect of concurrent Alzheimer-type pathology, and the ratio of 4R to 3R tau was measured in detergent-insoluble tau fractions. Insoluble tau from PSP was not composed exclusively of 4R tau. All brains had a mixture of 4R and 3R tau, but the ratio was different in Alzheimer's disease and PSP. In Alzheimer's disease there was less 4R than 3R tau, whereas the ratio was reversed in PSP. In PSP cases with concurrent Alzheimer-type pathology, the ratio of 4R to 3R was intermediate between Alzheimer's disease and PSP. The H1 haplotype had no effect on the 4R to 3R ratio or on tau and amyloid burdens. In summary, the H1 haplotype does not have a major influence on the pathological or biochemical phenotype of PSP.

Frequency of a tau genotype in amyotrophic lateral sclerosis

“…Previous studies have identified a strong association between the dinucleotide repeat polymorphism A0 and the risk of PSP, CBD and FTD [11 -13]. Remarkably, reports in PSP have shown no relation of the A0/A0 genotype to the biochemical characteristics such as tau deposit composition or to the clinical phenotype [14]. Also in ALS, we found no association of the A0/A0 genotype with the age and site of disease onset or the presence of dementia.…”

The Tau N279K Exon 10 Splicing Mutation Recapitulates Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 Tauopathy in a Mouse Model

“…Specifically, this group of diseases may include PSP, CBD, argyrophilic grain disease, and other FTDP-17 diseases resulting from exon 10 splicing mutations (Mailliot et al, 1998;Sergeant et al, 1999;Arai et al, 2001;Liu et al, 2001;Katsuse et al, 2003;Morris et al, 2003). These tauopathies all have similar characteristics of astrocytic and neuronal tau accumulation, predominantly 4R insoluble tau and motor and cognitive deficits.…”

Co-Localization of Glycogen Synthase Kinase-3 with Neurofibrillary Tangles and Granulovacuolar Degeneration in Transgenic Mice

“…All blots were incubated with a blocking solution containing 5% nonfat milk, 0.1% goat serum and 0.1% Tween-20 in TBS, incubated with various antibodies, and washed as previously described. 5,9,33 The washed blots were incubated for 1 hour at room temperature with peroxidase-conjugated, goat anti-rabbit (1:4000, Chemicon, Temecula, CA), anti-mouse IgG (1:2000, Bio Rad, Hercules, CA), followed with washing and detection of bound antibodies with the enhanced chemiluminescence system (ECL plus; Amersham Biosciences, Piscataway, NJ). Immunoreactivity of GSK3 proteins was analyzed from scanned films using MCID software (Imaging Research Inc., Ontario, Canada).…”