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Ann Clin Transl Neurol. 2015 Mar;2(3):278-88. doi: 10.1002/acn3.176. Epub 2015 Jan 23.

Anti-tau antibody reduces insoluble tau and decreases brain atrophy.

Author information

1
Department of Neurology, Washington University School of Medicine St. Louis, Missouri, 63110 ; Hope Center for Neurological Disorders, Washington University School of Medicine St. Louis, Missouri, 63110 ; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine St. Louis, Missouri, 63110.
2
Department of Psychiatry, Washington University School of Medicine St. Louis, Missouri, 63110 ; Department of Genetics, Washington University School of Medicine St. Louis, Missouri, 63110.
3
Department of Psychiatry, Washington University School of Medicine St. Louis, Missouri, 63110 ; The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine St. Louis, Missouri, 63110.
4
Department of Neurology and Neurotherapeutics, University of Texas, Southwestern Medical Center Dallas, Texas, 75390.

Abstract

OBJECTIVE:

We previously found a strong reduction in tau pathology and insoluble tau in P301S tau transgenic mice following intracerebroventricular infusion of the anti-tau antibody HJ8.5. We sought to determine the effects of HJ8.5 in the same model following peripheral administration.

METHODS:

The primary objective was to determine if HJ8.5 administered at a dose of 50 mg kg(-1) week(-1) by intraperitoneal (IP) injection to 6-month-old P301S mice for 3 months would influence phospho-tau (p-tau) accumulation, tau insolubility, and neurodegeneration.

RESULTS:

Treatment with HJ8.5 at 50 mg/kg showed a very strong decrease in detergent-insoluble tau. Importantly, HJ8.5 significantly reduced the loss of cortical and hippocampal tissue volumes compared to control treated mice. HJ8.5 treatment reduced hippocampal CA1 cellular layer staining with the p-tau antibody AT8 and thio-S-positive tau aggregates in piriform cortex and amygdala. Moreover, mice treated with HJ8.5 at 50 mg/kg showed a decrease in motor/sensorimotor deficits compared to vehicle-treated mice. Some effects of HJ8.5, including reduction in brain atrophy, and p-tau immunostaining were also seen with a dose of 10 mg kg(-1) week(-1). In BV2-microglial cells, we observed significantly higher uptake of P301S tau aggregates in the presence of HJ8.5. HJ8.5 treatment also resulted in a large dose-dependent increase of tau in the plasma.

INTERPRETATION:

Our results indicate that systemically administered anti-tau antibody HJ8.5 significantly decreases insoluble tau, decreases brain atrophy, and improves motor/sensorimotor function in a mouse model of tauopathy. These data further support the idea that anti-tau antibodies should be further assessed as a potential treatment for tauopathies.

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