ArticleProceedings of the National Academy of Sciences of the United States of America2023
Structure-based design of nanobodies that inhibit seeding of Alzheimer's patient-extracted tau fibrils.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 45 citations in OpenAlex.
- A water-pinning hotspot drives templated tau aggregation.bioRxiv : the preprint server for biology · 2026Article
- Amyloid fibril polymorphism: Structural mechanisms of assembly and the links to disease.Current opinion in structural biology · 2026Review
- Targeting vascular inflammation and endothelial dysfunction with nanobodies: emerging therapeutic strategies for cardiovascular disease.Frontiers in immunology · 2026Review
- Nanobody Therapeutics in Alzheimer's Disease: From Molecular Mechanisms to Translational Approaches.Antibodies (Basel, Switzerland) · 2025Review
- Nanobodies targeting hnRNPA2/B1 and tau.bioRxiv : the preprint server for biology · 2025Article
- Beyond amyloid: nanobody-mediated neuroinflammatory therapy for Alzheimer's disease.Translational neurodegeneration · 2025Review
- Anti-tau VHH therapy against PHF6: a safe approach to slowing the phenotype of tau pathology.Alzheimer's research & therapy · 2025Article
- Targeting RAGE with Nanobodies for Molecular Imaging of Cancers and Alzheimer's Disease.Advanced biology · 2025Article
- Incidental vs. Engineered Nanoparticles in Alzheimer's and Parkinson's Disease: Pathological Pathways and Therapeutic Interventions.Nano research · 2025Article
- Technetium-99m-Labeled Fibroblast Activation Protein-Targeted Nanobody Radiotracer: from Preclinical Development to Clinical Translation in Cancer Imaging.ACS pharmacology & translational science · 2025Article
- Crossing Barriers: Advancements in Macromolecular Therapeutics for Neurodegenerative Diseases and Strategies to Overcome the Blood-Brain Barrier.ACS pharmacology & translational science · 2025Review
- Extracellular Vesicles Administered via Intrathecal Injection Mediate Safe Delivery of Nucleic Acids to the Central Nervous System for Gene Therapy.Journal of extracellular vesicles · 2025Article
- Structure-specific Mini-Prion Model for Alzheimer's Disease Tau Fibrils.bioRxiv : the preprint server for biology · 2025Article
- A structure-guided antibody detects SOD1 oligomers in diverse ALS genotypes.bioRxiv : the preprint server for biology · 2025Article
- Trends in nanobody radiotheranostics.European journal of nuclear medicine and molecular imaging · 2025Review
- Generating the polymorph landscapes of amyloid fibrils using AI: RibbonFold.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Inhibition of tau neuronal internalization using anti-tau single domain antibodies.Nature communications · 2025Article
- Nanobody engineering: computational modelling and design for biomedical and therapeutic applications.FEBS open bio · 2025Review
- Second-generation anti-amyloid monoclonal antibodies for Alzheimer's disease: current landscape and future perspectives.Translational neurodegeneration · 2025Review
- Generation of nanobodies with conformational specificity for tau oligomers that recognize tau aggregates from human Alzheimer's disease samples.Biomaterials science · 2024Article
Corrections and comments
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Authors and funding
27 authors at 4 institutions in 2 countries.
Funding
Abstract
Despite much effort, antibody therapies for Alzheimer's disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include the difficulty of achieving specific affinity to critical targets, poor expression, and antibody aggregation caused by buried charges and unstructured loops. To overcome these challenges, we grafted previously determined sequences of fibril-capping amyloid inhibitors onto a camel heavy chain antibody scaffold. These sequences were designed to cap fibrils of tau, known to form the neurofibrillary tangles of AD, thereby preventing fibril elongation. The nanobodies grafted with capping inhibitors blocked tau aggregation in biosensor cells seeded with postmortem brain extracts from AD and progressive supranuclear palsy (PSP) patients. The tau capping nanobody inhibitors also blocked seeding by recombinant tau oligomers. Another challenge to the design of effective antibodies is their poor blood-brain barrier (BBB) penetration. In this study, we also designed a bispecific nanobody composed of a nanobody that targets a receptor on the BBB and a tau capping nanobody inhibitor, conjoined by a flexible linker. We provide evidence that the bispecific nanobody improved BBB penetration over the tau capping inhibitor alone after intravenous administration in mice. Our results suggest that the design of synthetic antibodies that target sequences that drive protein aggregation may be a promising approach to inhibit the prion-like seeding of tau and other proteins involved in AD and related proteinopathies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.