Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein.

ABSTRACT

BACKGROUND: A possible role of autoimmunity in Alzheimer disease pathogenesis has recently attracted increasing attention. Vaccination with amyloid-beta 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.