Seeding activity of skin misfolded tau as a biomarker for tauopathies.

Background: Tauopathies are a group of age-related neurodegenerative diseases characterized by the accumulation of pathologically hyperphosphorylated tau protein in the brain, leading to prion-like aggregation and propagation. They include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Currently, reliable diagnostic biomarkers that directly reflect the capability of propagation and spreading of misfolded tau aggregates in peripheral tissues and body fluids are lacking.
Methods: We utilized the seed-amplification assay (SAA) employing ultrasensitive real-time quaking-induced conversion (RT-QuIC) to assess the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies, including AD, PSP, CBD, and PiD, compared to normal controls.
Results: We found that the skin tau-SAA demonstrated a significantly higher sensitivity (75-80%) and specificity (95-100%) for detecting tauopathy, depending on the tau substrates used. Moreover, the increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients examined. Analysis of the end products of skin-tau SAA confirmed that the increased seeding activity was accompanied by the formation of tau aggregates with different physicochemical properties related to two different tau substrates used.
Conclusions: Overall, our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of misfolded tau in the skin could serve as a diagnostic biomarker for tauopathies.
Competing Interests: Declarations. Ethics approval and consent to participate: All procedures and protocols were monitored and approved by the Institutional Review Boards (IRBs) of University Hospitals Cleveland Medical Center, Banner Sun Health Research Institute, and IRCCS Institute of Neurological Sciences of Bologna. Written informed consent was obtained from all living subjects undergoing skin biopsy or from family members for skin autopsy. For post-mortem sample collection, we obtained the specimens with respect to the wishes of the deceased and their family, following all legal and ethical guidelines. For skin biopsy procedures, all participants provided their informed consent prior to their inclusion in the study. Consent for publication: All participants in this study have provided written informed consent for their data and samples to be used in this research. Participants were also informed that the results of this study may be published and that all data would be fully anonymized to protect confidentiality. Competing interests: Authors declare that they have no competing interests.
(© 2024. The Author(s).)