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Open Access 01-12-2019 | Heparin | Research

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

Authors: Jennifer A. Macdonald, Iraad F. Bronner, Lesley Drynan, Juan Fan, Annabelle Curry, Graham Fraser, Isabelle Lavenir, Michel Goedert

Published in: Acta Neuropathologica Communications | Issue 1/2019

Abstract

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 ²⁷⁵VQIINK²⁸⁰ and ³⁰⁶VQIVYK³¹¹, 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.

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Title: Assembly of transgenic human P301S Tau is necessary for neurodegeneration in murine spinal cord
Authors: Jennifer A. Macdonald
Iraad F. Bronner
Lesley Drynan
Juan Fan
Annabelle Curry
Graham Fraser
Isabelle Lavenir
Michel Goedert
Publication date: 01-12-2019
Publisher: BioMed Central
Keyword: Heparin
Published in: Acta Neuropathologica Communications / Issue 1/2019
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-019-0695-5

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

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