Recent evidence suggests that tau aggregates are not only neurotoxic, but also propagate in neurons acting as a seed for native tau aggregation. Prion-like tau transmission is now considered as an important pathogenic mechanism driving the progression of tau pathology in the brain. However, prion-like tau species have not been clearly characterized. To identify infectious tau conformers, here we prepared diverse tau aggregates and evaluated the effect on inducing intracellular tau-aggregation. Among tested, tau dimer containing P301L-mutation is identified as the most infectious form to induce tau pathology. Biochemical analysis reveals that P301L-tau dimer is covalently cross-linked with a disulfide bond. The relatively small and covalently cross-linked tau dimer induced tau pathology efficiently in primary neurons and also in tau-transgenic mice. So far, the importance of tau disulfide cross-linking has been overlooked in the study of tau pathology. Here our results suggested that tau disulfide cross-linking might play critical role in tau propagation by producing structurally stable and small tau conformers.
Bibliographical noteFunding Information:
This work was supported by an intramural funding from Korea Institute of Science and Technology (2E25240 and 2E25473), and grant funded by Ministry of Health & Welfare, Republic of Korea 1465016897. This research was also supported by the NRF and the WISET Grant funded by the Ministry of Science, MSIP under the Program for Returners into R&D (KW-2014-PPD-0076), Cooperative Research Program for Agriculture Science & Technology Development (PJ009103) by RDA, the Korea Atomic Energy Research Institute (KAERI) grant (Grant No. 698214-14) funded by Korea government (Ministry of Science, ICT and Future Planning) and National Medical Research Council grant (NMRC/ CBRG/0015/2012).
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