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Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Anti-Tau Antibodies that Block Tau Aggregate Seeding In Vitro Markedly Decrease Pathology and Improve Cognition In Vivo. Neuron. 2013 Oct 16;80(2):402-14. PubMed.
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This paper is really interesting – antibodies directed against tau reduced tau pathology in mice expressing a mutant, aggregating form of human tau. The antibody appears to both prevent the formation of extracellular tau aggregates as well as sequester pathological extracellular tau, reducing internalization of the aggregates by nearby neurons. Excitingly, this suggests that antibody-based therapies may be able to stop the progressive spread of tau tangles in the brains of those affected by Alzheimer's disease. However, more work will need to be done to determine the mechanism by which the tau/antibody complexes are cleared from the brain, and to understand how the antibody is able to reduce tau phosphorylation.
View all comments by Amy PoolerEmory University
The data in this study look convincing, and send the encouraging message that tauopathy, an intracellular proteopathy, can indeed be mitigated by an agent that appears to intercept seeds extracellularly. Hence, it may not be necessary for therapeutic agents to enter the cell to be effective.
View all comments by Lary WalkerDZNE, German Center for Neurodegenerative Diseases
This work is fantastic. It explains why antibody therapy might work for tau pathology, which was a matter of debate in the past. Einar Sigurdsson's group at NYU had shown that antibodies against tau can somehow reduce the pathology, but it was not clear to many observers how the antibodies would reach tau, which, after all, is mostly inside neurons. This new study shows that the antibodies only have to reach extracellular tau, and since this is in some equilibrium with intracellular tau, the antibodies have the potential to reduce tau levels and aggregation. The work provides a rationale for antibody-based therapeutic approaches to tauopathies, such as AD, FTD, and more. The one caveat I have is the description of protein transfer between cells as "prion like". Numerous proteins can be transferred across cellular membranes by well-known mechanisms, so I see no need to invoke "prions."
View all comments by Eckhard MandelkowWestern Illinois University
The behavioral data seems pretty weak. I'm not entirely convinced this study shows that reducing tauopathy improves cognition.
View all comments by Martin FordeNIMH
This is a very interesting study. It offers an innovative approach with a convincing set of data on neutralization of toxic tau protein in intact brain with anti-tau antibody treatment. Even though the unanswered questions for now preclude any legitimate therapeutic forecasts, the remarkable drop in tau loading described herein with inhibition of its spread are highly promising. Let us keep hopes high for similar outcomes and more robust behavioral data from experiments with systemic immunization.
View all comments by Saak V. OvsepianKULeuven
This is excellent work allowing me to pitch two points:
1. Is there no need to target phosphorylated or conformational tau epitopes, as linear "naked" ones appear to work fine, at least in mice?
2. This is confirmation of what we thought all along, namely that antibodies need not reach into the neuronal cytoplasm, which is tricky to accomplish in any cell.
But major questions remain. How-and why-does tau leave the neuron? And how can extracellular tau be in equilibrium with cytoplasmic tau?
Finally, I second Eckhard's motion that there is no real need to invoke the buzz-word "prion" to explain the observations. This makes them no less interesting.
View all comments by Fred Van LeuvenUniversity of Edinburgh
This is a very interesting paper contributing to the growing body of evidence that passive immunotherapy may be able to prevent the spread of pathological forms of tau. There have been several promising studies on this concept, but in this paper, Yanamandra and colleagues take it to the next level by trying to address the mechanism responsible for the benefits of immunotherapy, hypothesizing that extracellular aggregated tau seeds are a key component of pathogenesis that can be targeted. They very elegantly show that infusion of several anti-tau antibodies into the P301S mouse model of tauopathy reduces the ability of the treated P301S brain homogenates to induce aggregation of tau in HEK cells expressing aggregate-prone tau. It is difficult to interpret the histological and behavioral improvements in the treated P301S animals as necessarily related to prevention of extracellular tau seeding, because these mice express tau throughout the brain. Thus the benefits of treatment could be due to a general reduction in soluble tau levels by antibody treatment rather than to the specific prevention of extracellular seeding. However, based on the findings presented in this paper, it will be possible to answer these questions in future studies.
View all comments by Tara Spires-JonesThis is a very interesting paper. Regarding phosphorylated tau that has been shown to be secreted via various mechanisms from dendrites (e.g., via exosomes in association with proteins such as fyn), does anyone know whether the focal tau deposits immobilize and stay in the extracellular space or if some are able to transfer (e.g., by endocytosis) into a neuron synapsing onto the dendrite?
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