Tauopathy-like Abnormalities and Neurologic Deficits in Mice Immunized With Neuronal Tau Protein

Background A possible role of autoimmunity in Alzheimer disease pathogenesis has recently attracted increasing attention. Vaccination with amyloid-β peptide was reported to cause marked reduction in amyloid deposition, but it also induced encephalitis. Not much is known regarding neurofibrillary tangle–related autoimmune effects. Objective To use the main component of tangles—microtubule-associated tau protein—to test the feasibility of active induction of a neuroautoimmune disorder in mice. Design Prospective, randomized controlled animal study. Setting University medical center research laboratory. Subjects Female C57BL/6 mice. Interventions Inoculation with recombinant human tau protein emulsified in complete Freund adjuvant and with pertussis toxin. Main Outcome Measures Clinical, immunologic, pathologic, and behavioral evaluations were performed. Results Vaccination with tau protein induced histopathologic features of Alzheimer disease and tauopathies, indicated by the presence of neurofibrillary tangle–like structures, axonal damage, and gliosis. Also, mononuclear infiltrates without demyelination in the central nervous system, accompanied by neurologic deficits (such as a limp tail and limb paralysis), were observed. Anti–tau antibodies were detected in the serum of tau-immunized mice. Conclusions These results provide a link between tau autoimmunity and tauopathy-like abnormalities and indicate potential dangers of using tau for immunotherapy. This experimental autoimmune tauopathy-like model is due to a pathogenic immune response against an intraneuronal antigen and is not related to myelin antigens.