Truncation of tau at E391 promotes early pathologic changes in transgenic mice.

Proteolytic cleavage of tau at glutamic acid 391 (E391) is linked to the pathogenesis of Alzheimer disease (AD). This C-terminal-truncated tau species exists in neurofibrillary tangles and abnormal neurites in the brains of AD patients and may potentiate tau polymerization. We generated a mouse model that expresses human tau truncated at E391 to begin to elucidate the role of this C-terminal-truncated tau species in the development of tau pathology. Our results show that truncated but otherwise wild-type human tau is sufficient to drive pretangle pathologic changes in tau, including accumulation of insoluble tau, somatodendritic redistribution, formation of pathologic conformations, and dual phosphorylation of tau at sites associated with AD pathology. In addition, these mice exhibit atypical neuritic tau immunoreactivity, including abnormal neuritic processes and dystrophic neurites. These results suggest that changes in tau proteolysis can initiate tauopathy.