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Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy

Overview of attention for article published in Molecular Neurodegeneration, August 2016
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  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (87th percentile)
  • High Attention Score compared to outputs of the same age and source (86th percentile)

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1 news outlet
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1 patent

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Title
Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy
Published in
Molecular Neurodegeneration, August 2016
DOI 10.1186/s13024-016-0126-z
Pubmed ID
Authors

Erin E. Congdon, Yan Lin, Hameetha B. Rajamohamedsait, Dov B. Shamir, Senthilkumar Krishnaswamy, Wajitha J. Rajamohamedsait, Suhail Rasool, Veronica Gonzalez, Josien Levenga, Jiaping Gu, Charles Hoeffer, Einar M. Sigurdsson

Abstract

A few tau immunotherapies are now in clinical trials with several more likely to be initiated in the near future. A priori, it can be anticipated that an antibody which broadly recognizes various pathological tau aggregates with high affinity would have the ideal therapeutic properties. Tau antibodies 4E6 and 6B2, raised against the same epitope region but of varying specificity and affinity, were tested for acutely improving cognition and reducing tau pathology in transgenic tauopathy mice and neuronal cultures. Surprisingly, we here show that one antibody, 4E6, which has low affinity for most forms of tau acutely improved cognition and reduced soluble phospho-tau, whereas another antibody, 6B2, which has high affinity for various tau species was ineffective. Concurrently, we confirmed and clarified these efficacy differences in an ex vivo model of tauopathy. Alzheimer's paired helical filaments (PHF) were toxic to the neurons and increased tau levels in remaining neurons. Both toxicity and tau seeding were prevented by 4E6 but not by 6B2. Furthermore, 4E6 reduced PHF spreading between neurons. Interestingly, 4E6's efficacy relates to its high affinity binding to solubilized PHF, whereas the ineffective 6B2 binds mainly to aggregated PHF. Blocking 4E6's uptake into neurons prevented its protective effects if the antibody was administered after PHF had been internalized. When 4E6 and PHF were administered at the same time, the antibody was protective extracellularly. Overall, these findings indicate that high antibody affinity for solubilized PHF predicts efficacy, and that acute antibody-mediated improvement in cognition relates to clearance of soluble phospho-tau. Importantly, both intra- and extracellular clearance pathways are in play. Together, these results have major implications for understanding the pathogenesis of tauopathies and for development of immunotherapies.

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X Demographics

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 55 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United States 1 2%
Unknown 54 98%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 14 25%
Researcher 13 24%
Student > Bachelor 6 11%
Professor 3 5%
Student > Postgraduate 3 5%
Other 7 13%
Unknown 9 16%
Readers by discipline Count As %
Neuroscience 12 22%
Biochemistry, Genetics and Molecular Biology 11 20%
Agricultural and Biological Sciences 11 20%
Medicine and Dentistry 3 5%
Pharmacology, Toxicology and Pharmaceutical Science 1 2%
Other 4 7%
Unknown 13 24%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 13. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 19 July 2023.
All research outputs
#2,489,385
of 24,220,739 outputs
Outputs from Molecular Neurodegeneration
#304
of 902 outputs
Outputs of similar age
#43,189
of 342,888 outputs
Outputs of similar age from Molecular Neurodegeneration
#3
of 15 outputs
Altmetric has tracked 24,220,739 research outputs across all sources so far. Compared to these this one has done well and is in the 89th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 902 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 15.6. This one has gotten more attention than average, scoring higher than 65% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 342,888 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 87% of its contemporaries.
We're also able to compare this research output to 15 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 86% of its contemporaries.