Rescue of pathology and cognitive impairment by tau immunotherapy at a moderate to severe stage of the disease in 3xTg-alzheimer's disease mice

Abstract

Neurofibrillary tangles which are made up of abnormally hyperphosphorylated tau are a hallmark brain lesion of Alzheimer disease (AD) and other tauopathies. Unlike normal tau which interacts with tubulin and promotes its assembly into microtubules, the AD P-tau sequesters normal tau, disrupts microtubules, and serves as a template for its prion-like aggregation and spread. In a previous study we showed that targeting the amino terminal region of tau could rescue not only tau pathology and cognitive impairment but also could possibly reduce Aβ pathology in 3xTg-AD mice. Female 12-13 month old 3xTg-AD mice and age- and sex-matched control WT mice received 6 weekly intravenous injections of 15 micrograms of mouse monoclonal antibody (mAb) 43D to Tau6-18, mAb 77E9 to Tau184-195, a mixture of 43D and 77E9 or, as control, mouse IgG for 6 weeks. The day after the last injection the animals were subjected to several days of behavioral tests. On day 66 the animals received the 7thinjection of the antibody or control IgG. One half of the mice were sacrificed on day 72 and the remaining animals were tested for reference memory and by novel object location test at age ∼18 months. 3xTg-AD mice exhibited reference memory impairment and short-term memory deficit and higher level of anxiety than WT control mice. Passive immunization with 43D antibody completely rescued deficits in reference memory in Morris Water Maze and short-term memory in one-trial object recognition task. Passive immunization with antibody 77E9 rescued short-term memory impairment but did not show beneficial effect in spatial learning. At 18 months the 3xTg-AD mice treated with antibody 43D but not 77E9 showed a clear trend in rescue of short-term reference memory deficit. These studies show (1) that targeting of the amino terminal region, i.e. tau6-18, is more beneficial than tau184-195 region; (2) that the beneficial effect of passive immunotherapy can last at least ∼5 months in mice; and (3) that targeting the amino terminal region of tau is potentially an especially promising strategy for the treatment of AD and possibly other tauopathies.