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AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy.


ABSTRACT: Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the Fc domain of HJ8.5 is required for the therapeutic effect, we engineered single-chain variable fragments (scFvs) derived from HJ8.5 with variable linker lengths, all specific to human tau. Based on different binding properties, we selected two anti-tau scFvs and tested their efficacy in vivo by adeno-associated virus-mediated gene transfer to the brain of P301S-tg mice. The scFvs significantly reduced levels of hyperphosphorylated, aggregated tau in brain tissue of P301S-tg mice, associated with a decrease in detergent-soluble tau species. Interestingly, these mice showed substantial levels of scFvs in the cerebrospinal fluid without significant effects on total extracellular tau levels. Therefore, our study provides a novel strategy for anti-tau immunotherapeutics that potentially limits a detrimental proinflammatory response.

SUBMITTER: Ising C 

PROVIDER: S-EPMC5413341 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy.

Ising Christina C   Gallardo Gilbert G   Leyns Cheryl E G CEG   Wong Connie H CH   Jiang Hong H   Stewart Floy F   Koscal Lauren J LJ   Roh Joseph J   Robinson Grace O GO   Remolina Serrano Javier J   Holtzman David M DM  

The Journal of experimental medicine 20170417 5


Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the F<sub>c</sub> domain of HJ8.5 is required for the therapeutic effect, we engineered single-chain variable fragme  ...[more]

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