Anti‐tau antibody reduces insoluble tau and decreases brain atrophy

• Published in: Annals of clinical and translational neurology Vol. 2; no. 3; pp. 278 - 288
• Main Authors: Yanamandra, Kiran, Jiang, Hong, Mahan, Thomas E., Maloney, Susan E., Wozniak, David F., Diamond, Marc I., Holtzman, David M.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2015; BlackWell Publishing Ltd
• Subjects: Alzheimer's disease; Atrophy; Behavior; Enzymes; Glycerol; Immunoglobulins; Laboratories; Pathology; Proteins; Transgenic animals
• ISSN: 2328-9503; 2328-9503
• DOI: 10.1002/acn3.176

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.