A novel way to expand human-derived pathogenic tau seeds in a cell free system
MentorVirginia Man-Yee Lee, PhD
Tau aggregates (tauopathy seeds) enriched from the postmortem brains Alzheimer’s disease patients exhibit specific biological activity of inducing normal tau into misfolded pathological tau. But the quantity and quality of the tauopathy seeds are very much limited. In the study, we will explore the seeding mechanism of the human tau seeds using in vitro reactions for a better understanding of the pathogenesis of AD and other tauopathies. Moreover, we want to amplify tauopathy seeds in vitro by making use of the self-propagating features of them and promote future studies of tau pathology transmission.
Alzheimer’s disease (AD) is one of many neurodegenerative diseases associated specifically with pathological tau protein, which are collectively categorized as tauopathies. The tau aggregates observed in tauopathy exhibit biological activity of acting as ‘seeds’, which are capable of inducing normal tau protein to misfold into pathological aggregates and contribute to disease progression. We are able to experimentally model the sporadic development of tau pathology in cells and mice by using tau seeds extracted from human patient postmortem brains. While human-derived tau seeds are an extremely valuable experimental tool for elucidating the multitude of variables that affect tau pathogenesis and disease progression, an ongoing limitation in the field is the availability of brain tissue and the quality of extracted tau seeds. In this study, we aim to address this limitation by utilizing the self-propagating feature of pathological tau to amplify human-derived tau seeds in a cell-free system. Based on our previously established protocol, we plan to standardize the amplification reaction using AD-tau seeds with the goal of applying it to tau seeds derived from different tauopathies. We will determine whether the disease-specific biological activity of human-derived tau seeds are conserved in the amplified material using recently developed tau-spreading models, which enable us to differentiate tau seeds from different tauopathies based on their unique bioactivities. Successfully amplifying tau seeds will not only offer novel insight into the formation of misfolded tau aggregates, but also help to overcome the limited quantity and consistency of human-derived tau, greatly extending our ability to perform large-scale studies of the mechanisms underlying tau pathology.