Brain homogenates from human tauopathies induce tau inclusions in mouse brain

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 23; pp. 9535 - 9540
• Main Authors: Clavaguera, Florence, Akatsu, Hiroyasu, Fraser, Graham, Crowther, R. Anthony, Frank, Stephan, Hench, Jürgen, Probst, Alphonse, Winkler, David T., Reichwald, Julia, Staufenbiel, Matthias, Ghetti, Bernardino, Goedert, Michel, Tolnay, Markus
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences 04-06-2013; National Acad Sciences
• Subjects: Aged; Aged, 80 and over; Alzheimer's disease; Alzheimers disease; Animals; Antibodies; Biological and medical sciences; Biological Sciences; Blotting, Western; Brain; Brain - metabolism; Brain - pathology; Crosses, Genetic; Female; Fundamental and applied biological sciences. Psychology; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neurodegenerative diseases; Neurons; Pathology; Protein isoforms; Rodents; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies; Tauopathies - physiopathology; Tissue Extracts - administration & dosage; Tissue Extracts - pharmacology; Transgenic plants; Transplantation, Heterologous; Vertebrates: nervous system and sense organs; Human; Vertebrata; Mammalia; Tau protein; Mouse; Animal; Rodentia; Central nervous system; Encephalon
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1301175110

Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer’s disease, tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer’s disease and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. We previously demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. Here we injected brain extracts from humans who had died with various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice. Argyrophilic tau inclusions formed in all cases and following the injection of the corresponding brain extracts, we recapitulated the hallmark lesions of AGD, PSP and CBD. Similar inclusions also formed after intracerebral injection of brain homogenates from human tauopathies into nontransgenic mice. Moreover, the induced formation of tau aggregates could be propagated between mouse brains. These findings suggest that once tau aggregates have formed in discrete brain areas, they become self-propagating and spread in a prion-like manner.