Evidence for different seeding activities of misfolded tau in classical and rapidly progressive Alzheimer's disease.

Alzheimer's disease (AD) may display various clinical phenotypes with different disease progressions, such as rapidly progressive Alzheimer's disease (rpAD) type. The reason for clinical heterogeneity is still unknown and not predictable. Here, we subjected frontal cortex-derived tau seeds from classical AD, rpAD patients and controls to tau real-time quaking-induced conversion (RT-QuIC) assay analysis and examined biochemical properties, toxicity, and the morphology of tau fibrils generated during the RT-QuIC applying a cell-based assay and transmission electron microscopy (TEM). We observed seeding activity of misfolded tau protein in AD patients, which was significantly higher than in control cases. Additionally, the RT-QuIC signal response revealed differences between AD cases with a classical clinical phenotype and those with a rapidly progressive course of the disease (rpAD). The RT-QuIC reaction seeded with brain from rpAD exhibited a shorter lag phase, higher area under the curve and a higher seeding end point dilution compared to classical AD, independent from the Braak stage. The cellular toxicity of thioflavin T-positive RT-QuIC products from rpAD-seeded reactions was higher compared to those seeded by classical AD and controls. Morphological characterization of brain tissue-seeded RT-QuIC end-products via TEM showed that tau fibrils derived from rpAD seeded reactions revealed subtly different morphologies compared to classical AD. The study provides evidence for the existence of different tau assemblies in AD with different progression rates. As an alternative explanation, differences in the amounts of misfolded seed or the presence of other co-factors might influence the seeding activity of tau in AD and rpAD patients.