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Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model
Open accessAbstract
Alzheimer's disease is characterized by the deposition of amyloid-β as extracellular plaques and hyperphosphorylated tau as intracellular neurofibrillary tangles. Tau pathology characterizes not only Alzheimer's disease, but also many other tauopathies, presenting tau as an attractive therapeutic target. Passive tau immunotherapy has been previously explored; however, because only a small fraction of peripherally delivered antibodies crosses the blood-brain barrier, enters the brain and engages with tau that forms intracellular aggregates, more efficient ways of antibody delivery and neuronal uptake are warranted. In the brain, tau exists as multiple isoforms. Here, we investigated the efficacy of a novel 2N tau isoform-specific single chain antibody fragment, RN2N, delivered by passive immunization in the P301L human tau transgenic pR5 mouse model. We demonstrate that, in treated mice, RN2N reduces anxiety-like behaviour and phosphorylation of tau at distinct sites. When administration of RN2N was combined with focused ultrasound in a scanning mode (scanning ultrasound), RN2N delivery into the brain and uptake by neurons were markedly increased, and efficacy was significantly enhanced. Our study provides evidence that scanning ultrasound is a viable tool to enhance the delivery of biologics across the blood-brain barrier and improve therapeutic outcomes and further presents single-chain antibodies as an alternative to full-length antibodies.
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“Moreover, antibody fragments have been shown to reduce tau levels in vivo225,226.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [225]
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Metadata
- Authors
- Nisbet, R. M., Van der Jeugd, A., Leinenga, G., Evans, H. T., Janowicz, P. W., & Götz, J.
- Affiliations
- The University of Queensland (AU)
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia Campus, Brisbane, QLD 4072, Australia
- Corresponding author
- Götz, Jürgen
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-04-04
- Volume
- 140
- Issue
- 5
- Pages
- 1220-1230
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC5405237
- OpenAlex
- W2605011026
- Cited by
- 187
- References
- 46
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 22 · 2023: 17 · 2022: 20 · 2021: 31 · 2020: 25 · 2019: 17 · 2018: 25 · 2017: 8
- FWCI
- 15.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- estate of Dr Clem Jones AO
- State Government of Queensland
- Federal Government of Australia (ACT900116)
- The Brain Foundation
- Australian Research Council (DP13300101932)
- National Health and Medical Research Council of Australia (APP1037746, APP1003150)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- tau pathology, Alzheimer's disease, single-chain antibody, passive immunotherapy, blood-brain barrier, tau phosphorylation, anxiety-like behavior, tau immunotherapy
- MeSH terms
- Animals, Antibodies, Brain, Combined Modality Therapy, Disease Models, Animal, Humans, Immunization, Passive, Mice, Transgenic, Neurons, Phosphorylation, Ultrasonic Therapy, tau Proteins, Maze Learning, Protein Isoforms, Tauopathies, Mice
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