4R-Tau seeding activity unravels molecular subtypes in patients with Progressive Supranuclear Palsy

Abstract

Progressive Supranuclear palsy (PSP) is a 4-repeat (4-R) tauopathy. We hypothesized that the molecular diversity of tau could explain the heterogeneity seen in PSP disease progression. To test this hypothesis, we performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients. We found a correlation between the HMW-Tau species and tau seeding capacity in the primary motor cortex, where we confirmed that an elevated 4R-Tau seeding activity correlates with a shorter disease duration. To identify factors that contribute to these differences, we performed proteomic and spatial transcriptomic analysis that revealed key mechanistic pathways, in particular those involving the immune system, that defined patients demonstrating high and low tau seeding capacity. These observations suggest that differences in the tau seeding activity may contribute to the considerable heterogeneity seen in disease progression of patients suffering from PSP.

The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases

“…Further use of high-resolution quantitative measurement techniques, such as X-ray spectromicroscopy and inductively coupled plasma mass spectrometry (ICP-MS), would likewise enhance our understanding of neurodegenerative pathological iron deposition. Moreover, the dynamic nature of these interactions highlights the need for a more systematic design of MRI studies in combination with biomarker testing of the patients involved, such as PET or real-time quaking-induced conversion (RT-QuIC) [184], for delineation of iron dysregulation over the course of disease. Based on these findings, we propose that the heterogeneity and complexity of iron involvement in these diseases demonstrate the need for more intricate disease-specific iron targets or strategies for more defined patient sub-cohorts for better clinical outcomes.…”

Phenotype parallels protein seeding capacity in neurodegenerative diseases

“…But these HMW‐Tau species are not only found in AD brains. Our group has recently described that in the brains of patients with progressive supranuclear palsy (PSP), a four repeat (4R) tauopathy, these species could also play a role in the heterogeneity seen in the disease [ 8 ].…”