ArticleMolecular neurodegeneration2016
Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy.
Article in Molecular neurodegeneration, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 64 citations in OpenAlex.
- A single-domain antibody targets aggregation-prone region of α-synuclein to reduce synucleinopathy, rescue neurodegeneration and improve function.bioRxiv : the preprint server for biology · 2026Article
- Tau pSer396 and pSer404 Define Distinct Epitope Regions Linked to Different Antibody Functions.bioRxiv : the preprint server for biology · 2026Article
- Role of apolipoprotein E4 in alzheimer's disease pathogenesis and emerging therapeutic strategies.Metabolic brain disease · 2025Review
- Clearing truncated tau protein restores neuronal function and prevents microglia activation in tauopathy mice.Cell reports · 2025Article
- Twenty years of therapeutic development in tauopathy mouse models: a scoping review.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Prion and "Prion-Like" Detection: From Conventional Methods to Microfluidics or Lab-on-Chip Platforms to Monitor Seeding and Spreading of Misfolded Proteins.Sub-cellular biochemistry · 2025Review
- Neuronal hypofunction and network dysfunction in a mouse model at an early stage of tauopathy.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Anti-tau single domain antibodies clear pathological tau and attenuate its toxicity and related functional defects.Cell death & disease · 2024Article
- Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury.Molecular neurodegeneration · 2024Article
- Single-domain antibody-based protein degrader for synucleinopathies.Molecular neurodegeneration · 2024Article
- Single-Domain Antibody-Based Protein Degrader for Synucleinopathies.bioRxiv : the preprint server for biology · 2024Article
- Tau Immunotherapies for Alzheimer's Disease and Related Tauopathies: Status of Trials and Insights from Preclinical Studies.Journal of Alzheimer's disease : JAD · 2024Review
- Tau-targeting therapies for Alzheimer disease: current status and future directions.Nature reviews. Neurology · 2023Review
- Single-domain antibody-based noninvasive in vivo imaging of α-synuclein or tau pathology.Science advances · 2023Article
- Comprehensive evaluation of human-derived anti-poly-GA antibodies in cellular and animal models ofProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Review
- Targeting tau only extracellularly is likely to be less efficacious than targeting it both intra- and extracellularly.Seminars in cell & developmental biology · 2022Review
- Review
- Increased neuronal activity in motor cortex reveals prominent calcium dyshomeostasis in tauopathy mice.Neurobiology of disease · 2021Article
- Tau immunotherapies: Lessons learned, current status and future considerations.Neuropharmacology · 2020Review
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
backgroundA 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.
resultsSurprisingly, 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.
conclusionsOverall, 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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