Tau immunotherapy rescues cognitive impairment by clearing extracellular tau

Background Alzheimer’s disease (AD) is histopathologically characterized by loss of neuronal connectivity associated with extensive tau and Abeta pathologies. Tau immunization can inhibit the seeding and spread of tau pathology and reduce not only tau but also Abeta pathology and rescue cognitive impairment in transgenic tau overexpression mouse models of AD pathology. The specific objective of this study was to determine if tau immunization in wild type aged mice, which like AD patients do not overexpress either APP or tau, can rescue cognitive impairment. Method We investigated the effect of immunization with monoclonal antibody 77E9 against tau 184‐195 in 18month‐old male C57 BL/6 wild type (WT) mice, 15 microgram/200 microliter intravenous weekly injection for 6 weeks or once every four weeks injection for 24 weeks; mice injected with mouse IgG were used as controls. Result We found (1) that tau immunization did not significantly alter the level of brain tau as tested by Western blots developed with 77E9 or with rabbit polyclonal tau antibodies 92e or 134d to total tau, (2) that aged mice were impaired as compared with the young animals as determined by novel object recognition test and Morris water maze test, and showed dendritic and synaptic deficits and (3) that tau immunization rescued these deficits and cognitive impairment. Conclusion The therapeutic beneficial effect of immunization with tau antibody is probably through the restoration of neuronal connectivity due to clearance of primarily extracellular tau. Tau immunotherapy is thus likely to be effective only in those conditions where a reduction of extracellular tau will benefit.