Assembly of transgenic human P301S Tau is necessary for neurodegeneration in murine spinal cord

• Published in: Acta neuropathologica communications Vol. 7; no. 1; p. 44
• Main Authors: Macdonald, Jennifer A, Bronner, Iraad F, Drynan, Lesley, Fan, Juan, Curry, Annabelle, Fraser, Graham, Lavenir, Isabelle, Goedert, Michel
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18.03.2019; BioMed Central; BMC
• Subjects: Animal genetic engineering; Animals; Antibodies; Anticoagulants; Brain; Death; EDTA; Genetic engineering; Humans; Kinases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nervous system diseases; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - pathology; Neurons; Rodents; Sarkosyl-insoluble tau; Spinal Cord - pathology; Tau assembly; Tau filaments; tau Proteins - genetics; Tauopathies - genetics; Tauopathies - pathology; Tauopathy; β-Sheet structure; Tau assembly; Tau filaments; Tauopathy; β-Sheet structure; Neurodegeneration; Sarkosyl-insoluble tau
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-019-0695-5

A pathological pathway leading from soluble monomeric to insoluble filamentous Tau is characteristic of many human neurodegenerative diseases, which also exhibit dysfunction and death of brain cells. However, it is unknown how the assembly of Tau into filaments relates to cell loss. To study this, we first used a mouse line transgenic for full-length human mutant P301S Tau to investigate the temporal relationship between Tau assembly into filaments, assessed using anti-Tau antibody AT100, and motor neuron numbers, in the lumbar spinal cord. AT100 immunoreactivity preceded nerve cell loss. Murine Tau did not contribute significantly to either Tau aggregation or neurodegeneration. To further study the relevance of filament formation for neurodegeneration, we deleted hexapeptides VQIINK and VQIVYK , either singly or in combination, from human 0N4R Tau with the P301S mutation. These hexapeptides are essential for the assembly of Tau into filaments. Homozygous mice transgenic for P301S Tau with the hexapeptide deletions, which expressed Tau at a similar level to the heterozygous line transgenic for P301S Tau, had a normal lifespan, unlike mice from the P301S Tau line. The latter had significant levels of sarkosyl-insoluble Tau in brain and spinal cord, and exhibited neurodegeneration. Mice transgenic for P301S Tau with the hexapeptide deletions failed to show significant levels of sarkosyl-insoluble Tau or neurodegeneration. Recombinant P301S Tau with the hexapeptide deletions failed to form β-sheet structure and filaments following incubation with heparin. Taken together, we conclude that β-sheet assembly of human P301S Tau is necessary for neurodegeneration in transgenic mice.