Ondrejcak T, Hu N-W, Coode E, Campbell T, Corbett GT, Doykov I, Mills K, Walsh DM, Livesey FJ, Rowan MJ, Klyubin I. Synaptotoxic effects of extracellular tau are mediated by its microtubule-binding region. 2025 Feb 24 10.1101/2025.02.21.639417 (version 1) bioRxiv.
Recommends
Please login to recommend the paper.
Comments
Washington University School of Medicine
This study investigated what tau species are capable of inducing synaptotoxicity, by measuring LTP in rats injected with AD brain extracts or with secretomes of iPSC-derived neurons from individuals with Down’s syndrome. The study design includes the immunodepletion or co-injection with any of five anti-tau antibodies targeting: tau’s mid-region (218-225, Tau5); the microtubule binding region (MTBR) and the adjacent pseudo repeat (referred as MTBR/R’) (369-381, Gen2B); another MTBR/R’ (396-410, Gen2A); the MTBR to C-terminal wide region (243-441, K9JA-polyclonal); and the C-terminal region (404-441, Tau46).
Briefly, whereas immunodepletion or co-injection with most of the antibodies attenuated LTP inhibition induced by the secretomes or AD brain extracts, only Tau46 targeting the extreme C-terminal region (404-441) was ineffective. That Tau46 did not rescue rat LTP is consistent with recent reports, including of tau-FRET aggregation rescued by several antibodies (Islam et al., 2025), and tau-filament formation with various length of recombinant tau (Lövestam et al., 2022), that propose the extreme C-terminal region of tau protects against tau aggregation.
Although the authors suggested MTBR/R’-containing and related fragments may be potent species to induce synaptotoxicity in this manuscript, it must be noted that the tau profiles in media from iPSC-derived neurons and brain extracts are different from the tau profiles in human extracellular space. Therefore, further studies would be necessary before potential therapeutics, especially immunotherapy, related to MTBR/R' could be considered.
References:
Islam T, Hill E, Abrahamson EE, Servaes S, Smirnov DS, Zeng X, Sehrawat A, Chen Y, Kac PR, Kvartsberg H, Olsson M, Sjons E, Gonzalez-Ortiz F, Therriault J, Tissot C, Del Popolo I, Rahmouni N, Richardson A, Mitchell V, Zetterberg H, Pascoal TA, Lashley T, Wall MJ, Galasko D, Rosa-Neto P, Ikonomovic MD, Blennow K, Karikari TK. Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer's disease. Nat Med. 2025 Feb;31(2):574-588. Epub 2025 Feb 10 PubMed.
Lövestam S, Koh FA, van Knippenberg B, Kotecha A, Murzin AG, Goedert M, Scheres SH. Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy. Elife. 2022 Mar 4;11 PubMed.
View all comments by Kanta HorieMake a Comment
To make a comment you must login or register.