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Human Tau Isoform Aggregation and Selective Detection of Misfolded Tau from Post-Mortem Alzheimer's Disease Brains

By Ling Wu, Zerui Wang, Shradha Ladd, Darren T. Dougharty, Sidharth S. Madhavan, Madeleine Marcus, Frances Henderson, W. Keith Ray, Christopher Tan, Sandra Siedlak, Jianyong Li, Richard F. Helm, Xiongwei Zhu, George S. Bloom, Wen-Quan Zou, Bin Xu

Posted 02 Jan 2020
bioRxiv DOI: 10.1101/2019.12.31.876946

Tau aggregates are present in a large number of neurodegenerative diseases known as "tauopathies", including Alzheimer's disease (AD). As there are six human tau isoforms in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions, we tested whether tau isoforms behave differently in aggregation. We discovered that all six tau isoforms are capable of forming PHF-tau like filaments and the 3R tau isoforms aggregate significantly faster than their 4R counterparts. We further mapped key segments of tau isoforms that contribute to their aggregation kinetics, where it was determined that microtubule binding domains R2 and R3 were the major contributors to tau aggregation. To evaluate the feasibility of using the six recombinant tau isoforms as substrates to amplify misfolded tau, we demonstrated that full-length human tau isoforms can seed and detect misfolded tau from the post-mortem AD brain tissues with high specificity by an ultrasensitive technology termed real-time quaking-induced conversion (RT-QuIC). Mass spectrometric analysis of PHF-tau samples extracted from AD brains identified peptides corresponding to all major forms of human brain tau isoforms along with a consensus hyperphosphorylated peptide near the C-terminus. Together, our findings not only reveal new aggregation kinetic properties of human tau isoforms, support the development of methods to quantitatively measure misfolded human tau isoforms in AD brains, but also uncover the capability of full-length human tau isoforms as substrates for "prion-like" tau seeding by RT-QuIC assays that may be used for new biomarker development for AD and other tauopathy diagnosis.

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