title: Truncation of tau at E391 promotes early pathologic changes in transgenic mice.
abstract: 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.
authors: Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA. pammcm@u.washington.edu
authors: Pamela J
authors: PJ
authors: McMillan
authors: Brian C
authors: BC
authors: Kraemer
authors: Linda
authors: L
authors: Robinson
authors: James B
authors: JB
authors: Leverenz
authors: Murray
authors: M
authors: Raskind
authors: Gerard
authors: G
authors: Schellenberg
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D027682:Cation Transport Proteins / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D018698:Glutamic Acid / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D016875:tau Proteins; D018698:Glutamic Acid; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases