Research ArticleTAUOPATHIES

Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy

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Science Translational Medicine  19 Apr 2017:
Vol. 9, Issue 386, eaal2029
DOI: 10.1126/scitranslmed.aal2029

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Tracking tau in mice and humans

Tauopathies, such as progressive supranuclear palsy and Alzheimer’s disease, are a group of neurodegenerative diseases characterized by the accumulation of aggregated forms of tau protein in the brain. Administration of anti-tau antibodies is a new treatment approach being tested for these diseases. Tau is present at high levels in the brain and low levels in the plasma. Peripheral administration of an anti-tau antibody markedly increased tau in the plasma of both transgenic mice expressing human tau and patients with tauopathy (Yanamandra et al.). The increase in plasma tau in mice correlated with an increase in brain extracellular and soluble tau.

Abstract

Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes. Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain.

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