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Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model.

ABSTRACT: Alzheimer's disease is characterized by the deposition of amyloid-? 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.

SUBMITTER: Nisbet RM

PROVIDER: S-EPMC5405237 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model.

Nisbet Rebecca M RM Van der Jeugd Ann A Leinenga Gerhard G Evans Harrison T HT Janowicz Phillip W PW Götz Jürgen J

Brain : a journal of neurology 20170501 5

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 ...[more]

PMID: 28379300

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Project description:Intracellular deposits of pathological tau are the hallmark of a broad spectrum of neurodegenerative disorders collectively known as tauopathies, with Alzheimer's disease, a secondary tauopathy, being further characterized by extracellular amyloid plaques. A major obstacle in developing effective treatments for tauopathies is the presence of the blood-brain barrier, which restricts the access of therapeutic agents to the brain. An emerging technology to overcome this limitation is the application of low-intensity ultrasound which, together with intravenously injected microbubbles, transiently opens the blood-brain barrier, thereby facilitating the delivery of therapeutic agents into the brain. Interestingly, even in the absence of therapeutic agents, ultrasound has previously been shown to reduce amyloid plaques and improve cognitive functions in amyloid-depositing mice through microglial clearance. Ultrasound has also been shown to facilitate the delivery of antibody fragments against pathological tau in P301L tau transgenic mice; however, the effect of ultrasound alone has not been thoroughly investigated in a tauopathy mouse model. Methods: Here, we performed repeated scanning ultrasound treatments over a period of 15 weeks in K369I tau transgenic mice with an early-onset tau-related motor and memory phenotype. We used immunohistochemical and biochemical methods to analyze the effect of ultrasound on the mice and determine the underlying mechanism of action, together with an analysis of their motor and memory functions following repeated ultrasound treatments. Results: Repeated ultrasound treatments significantly reduced tau pathology in the absence of histological damage. Associated impaired motor functions showed improvement towards the end of the treatment regime, with memory functions showing a trend towards improvement. In assessing potential clearance mechanisms, we ruled out a role for ubiquitination of tau, a prerequisite for proteasomal clearance. However, the treatment regime induced the autophagy pathway in neurons as reflected by an increase in the autophagosome membrane marker LC3II and a reduction in the autophagic flux marker p62, along with a decrease of mTOR activity and an increase in beclin 1 levels. Moreover, there was a significant increase in the interaction of tau and p62 in the ultrasound-treated mice, suggesting removal of tau by autophagosomes. Conclusions: Our findings indicate that a neuronal protein aggregate clearance mechanism induced by ultrasound-mediated blood-brain barrier opening operates for tau, further supporting the potential of low-intensity ultrasound to treat neurodegenerative disorders.

Dataset Information

Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model.

Publications

Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model.

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