Dysregulation of 3R:4R ratio causes tauopathy, and human neurons that recapitulate tau isoforms in health and disease will provide a platform for elucidating pathogenic processes involving tau pathology.

Alterations of the 4R tau to 3R tau ratio may be a key for tau-related neurodegeneration. To study the biological consequences in expression between tau splicing isoforms 4R and 3R, we analyzed the main neurobiological effects of inclusion of the repeat region coded by exon 10 in MAPT.

Four-repeat (4R-) tauopathies are a group of neurodegenerative diseases defined by cytoplasmic inclusions predominantly composed of tau protein isoforms with four microtubule-binding domains. Progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease or glial globular tauopathy belong to the group of 4R-tauopathies.

May 12, 2021 · CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields …

We compared the clinical characteristics of 3 repeat (3R) and 4 repeat (4R) tau-positive cases (tauopathies) presenting as behavior variant frontotemporal dementia (bv-FTD).

Sep 1, 2017 · Expression of the 3R isoform causes more profound axonal transport defects and locomotor impairments, culminating in a shorter lifespan than the 4R isoform. In contrast, the 4R isoform leads to greater neurodegeneration and impairments in learning and memory.

In order to test whether 4R-tau is a prime mediator of tauopathy, we developed ASOs that target human MAPT mRNA to increase the 4R:3R tau ratio. hTau mice were treated with continuous intraventricular infusion of saline, scrambled ASO, or 3R-to-4R MAPT mRNA splicing ASO for 28 days via osmotic pump.

Apr 9, 2024 · 3R/4R selective RT-QuIC seeding activity recapitulate spatial patterns expected in AD progression and correlate with global and regional histopathological burden of AD tau pathology.

Nov 9, 2013 · We suggest that changes in immunoreactivity to antibodies reflect aging of tau in tangles or PHFs, which are composed of both 3R and 4R tau isoforms. We also show that Pro-K treatment of sections after Ac and FA treatment is useful for unmasking buried epitopes.

May 25, 2010 · Results presented here provide compelling evidence that altering the equimolar ratio of 3R and 4R tau such that 4R tau predominates accelerates tau filament assembly and that even small amounts of 3R tau can significantly inhibit the 4R tau assembly.