p-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice

Alzheimer's disease (AD) is a proteinopathy characterized by the accumulation of beta-amyloid (A beta) and tau. To date, clinical trials indicate that A beta immunotherapy does not improve cognition. Consequently, it is critical to modulate other aspects of AD pathology. As such, tau represents an excellent target, as its accumulation better correlates with cognitive impairment. To determine the effectiveness of targeting pathological tau, with A beta pathology present, we administered a single injection of AT8, or control antibody, into the hippocampus of aged 3xTg-AD mice. Extensive data indicates that phosphorylated Ser(202) and Thr(205) sites of tau (corresponding to the AT8 epitope) represent a pathologically relevant target for AD. We report that immunization with AT8 reduced somatodendritic tau load, p-tau immunoreactivity, and silver stained positive neurons, without affecting A beta pathology. We also discovered that tau pathology soon reemerges post-injection, possibly due to persistent A beta pathology. These studies provide evidence that targeting p-tau may represent an effective treatment strategy: potentially in conjunction with A beta immunotherapy. (C) 2014 Published by Elsevier Ireland Ltd.