Fragments of Tau’s Microtubule Binding Region Mess with Synapses

When under stress, neurons crank out tau fragments, and many scientists blame this for the propagation of tangle pathology in Alzheimer’s disease. The fragments also directly compromise synapses they encounter along the way, according to a preprint posted February 24 on bioRxiv. Specifically, tau fragments containing the microtubule binding region and its adjacent C-terminal sequence wreaked havoc on synaptic plasticity when injected into rat brains. Scientists led by Michael Rowan and Igor Klyubin of Trinity College, Dublin, reported that whether extracted from induced neurons derived from a person with trisomy 21, or from AD brain tissue, tau fragments hobbled long-term potentiation in the rat brain. This could only be rescued with antibodies directed against the MTBR and C-terminal-adjacent regions, implicating these tau species in synaptotoxicity.

  • Tau fragments from trisomy 21 neurons inhibited synaptic function in rat brains.
  • The same was true when AD brain extracts were the source of tau.
  • Antibodies to tau’s MTBR and downstream sequences prevented these deficits.

"This study nicely extends our understanding of the deleterious effects of tau’s MTBR region, clearly demonstrates its synaptotoxicity, and also provides the field with new antibodies (detecting MTBR epitopes) as tools to block this cascade, which could be used as immunotherapies in the future," wrote Todd Cohen, University of North Carolina, Chapel Hill.

The findings jibe with a growing consensus that therapies aimed at MTBR-containing tau stand a better chance at curbing tauopathy in AD than those targeting its N-terminus, particularly after trials of N-terminally targeted antibodies failed (Mar 2021 conference news; Nov 2024 conference news). The MTBR region is essential for tau to aggregate, and the core of tau fibrils found in AD tangles and in some primary tauopathies contain part of this region along with an adjacent C-terminal sequence (Jul 2017 news; Qi et al., 2025). 

With a focus on tau’s influence on synapses, Rowan and Klyubin had previously reported that, either extracted from an AD brain or secreted from induced trisomy 21 neurons, human tau injected into the rat hippocampus stifled long-term potentiation there (Hu et al., 2018; Ondrejcak et al., 2023). Subsequent injection of an anti-tau antibody reversed this defect (Ondrejcak et al., 2024). The injected extracts were teeming with a gemish of tau fragments, leaving the toxic species a mystery.

In their new study, first author Tomas Ondrejcak and colleagues deployed distinct antibodies to narrow in on the toxic species. First, they collected tau secreted by cultured induced neurons derived from a person with Down’s syndrome, and injected them into the cerebral ventricles of rats. Electrophysiological recordings in live, though anesthetized, rats revealed that the secretions from trisomy 21 neurons, but not those from control cells, profoundly muffled long-term potentiation, a proxy for synaptic plasticity and memory. LTP happened normally when the scientists first immunodepleted the neuronal secretomes with Tau5, an antibody specific for tau’s mid-region. K9JA, an antibody whose broad epitope encompasses the MTBR and C-terminus of tau, also took the synaptotoxic wind out of tau’s sails. In contrast, immunodepletion with an antibody to the extreme C-terminus of tau provided no protection. 

The authors have not tested whether antibodies aimed at tau’s N-terminus can extinguish toxicity. This is because none of the tau fragments detected in the Ts21 secretome contained an N-terminus, Rowan explained. In fact, all detectable tau remnants lacked regions N-terminal to the mid-region.

To narrow down the harmful tau species further, the scientists generated two additional antibodies—Gen2A and Gen2B—that latch onto different epitopes immediately C-terminal to the MTBR domain, also known as the R’ region. Both antibodies completely blocked the LTP-inhibition of tau extracts. Together, the findings suggested that tau fragments containing the MTBR and C-terminal adjacent sequences were the ones damaging synaptic function. In support of this, injection of recombinant tau297-391, which includes the MTBR/R’ regions, also put the kibosh on LTP.

Similar results emerged when the scientists used aqueous extracts from two AD brain samples as the source of tau. Antibodies specific to tau’s mid-section or MTBR/R’ regions stymied anti-synaptic activity of these preparations.

Strikingly, the injected human tau lingered in the rat hippocampus for three weeks following injection, as did the damper it put on LTP. Even by this time point, injection of Tau5, Gen2A, or Gen2B antibodies into the rat brain restored LTP within just 15 minutes. It appears that MTBR/R’-containing tau loiters around synapses, where it exerts a prolonged effect that can be relieved with anti-tau antibodies.

LTP Rescue. Three weeks after injecting AD tau extracts into rat hippocampus, long-term potentiation following high-frequency stimulation (HFS) was still inhibited. Injection with Gen2A or Gen2B antibodies, but not IgG control antibodies, relieved this inhibition. [Courtesy of Ondrejcak et al., bioRxiv, 2025.]

Did these tau fragments poison synapses in monomer form? Rowan and Ondrejcak can’t be sure no soluble tau fragments aggregated after they were injected into the rat brain, but believe their findings demonstrate synaptotoxic effect of MTBR/R’-tau monomers. This fits with recombinant tau297-391 monomers potently inhibiting LTP, they wrote to Alzforum. “It doesn’t rule out the possibility that certain tau aggregates that include MTBR/R’ are equally or even more potent,” they wrote. “However, fibrillar tau bound within neurofibrillary tangles is less diffusible and unlikely to be active in our model.”

They view their findings as supportive of ongoing and future development of anti-tau therapeutics aimed squarely at tau’s MTBR/R’ domain.

Kanta Horie of Washington University in St. Louis cautioned that the profile of tau proteins secreted from induced neurons or extracted from AD brain samples might not be the same as those found in the extracellular space of the human brain. “Therefore, further studies would be necessary before potential therapeutics, especially immunotherapy, related to MTBR/R' could be considered,” he wrote (comment below).—Jessica Shugart

Comments

    • User Profile Image Kanta Horie
      Washington University School of Medicine
    • Posted:

    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.

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References

News Citations

  1. N-Terminal Tau Antibodies Fade, Mid-Domain Ones Push to the Fore
  2. Finally, Therapeutic Antibodies Start to Reduce Tangles
  3. Tau Filaments from the Alzheimer’s Brain Revealed at Atomic Resolution

Paper Citations

  1. Qi C, Lövestam S, Murzin AG, Peak-Chew S, Franco C, Bogdani M, Latimer C, Murrell JR, Cullinane PW, Jaunmuktane Z, Bird TD, Ghetti B, Scheres SH, Goedert M. Tau filaments with the Alzheimer fold in human MAPT mutants V337M and R406W. Nat Struct Mol Biol. 2025 Mar 5; Epub 2025 Mar 5 PubMed.
  2. Hu NW, Corbett GT, Moore S, Klyubin I, O'Malley TT, Walsh DM, Livesey FJ, Rowan MJ. Extracellular Forms of Aβ and Tau from iPSC Models of Alzheimer's Disease Disrupt Synaptic Plasticity. Cell Rep. 2018 May 15;23(7):1932-1938. PubMed.
  3. Ondrejcak T, Klyubin I, Hu NW, O'Malley TT, Corbett GT, Winters R, Perkinton MS, Billinton A, Prenderville JA, Walsh DM, Rowan MJ. Tau and Amyloid β Protein in Patient-Derived Aqueous Brain Extracts Act Concomitantly to Disrupt Long-Term Potentiation in Vivo. J Neurosci. 2023 Aug 9;43(32):5870-5879. Epub 2023 Jul 25 PubMed.
  4. Ondrejcak T, Klyubin I, Hu NW, Yang Y, Zhang Q, Rodriguez BJ, Rowan MJ. Rapidly reversible persistent long-term potentiation inhibition by patient-derived brain tau and amyloid ß proteins. Philos Trans R Soc Lond B Biol Sci. 2024 Jul 29;379(1906):20230234. Epub 2024 Jun 10 PubMed.

Further Reading

Primary Papers

  1. 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.

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