In vitro amplification of pathogenic tau conserves disease-specific bioactive characteristics
Autor: | Jennifer D. McBride, Bin Zhang, Kurt R. Brunden, Lakshmi Changolkar, Virginia M.-Y. Lee, Jeffrey J. Nirschl, Kevt’her Hoxha, John Q. Trojanowski, Hong Xu, Garrett S. Gibbons, Gerard D. Schellenberg, Mia O’Reilly, Soo-Jung Kim, Dawn M. Riddle, Anna Stieber |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Disease specific in vitro seeding Tau protein Primary Cell Culture tau Proteins Fibril Pathology and Forensic Medicine law.invention Progressive supranuclear palsy 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine law Alzheimer Disease mental disorders medicine tau strains Corticobasal degeneration Animals Cells Cultured Conserved Sequence Original Paper biology tauopathy tau spreading Gene Amplification food and beverages Brain Neurodegenerative Diseases Neurofibrillary Tangles medicine.disease Immunohistochemistry In vitro Cell biology Mice Inbred C57BL 030104 developmental biology Tauopathies Recombinant DNA biology.protein Neurology (clinical) Tauopathy Supranuclear Palsy Progressive 030217 neurology & neurosurgery |
Zdroj: | Acta Neuropathologica |
ISSN: | 1432-0533 0001-6322 |
Popis: | The microtubule-associated protein tau (tau) forms hyperphosphorylated aggregates in the brains of tauopathy patients that can be pathologically and biochemically defined as distinct tau strains. Recent studies show that these tau strains exhibit strain-specific biological activities, also referred to as pathogenicities, in the tau spreading models. Currently, the specific pathogenicity of human-derived tau strains cannot be fully recapitulated by synthetic tau preformed fibrils (pffs), which are generated from recombinant tau protein. Reproducing disease-relevant tau pathology in cell and animal models necessitates the use of human brain-derived tau seeds. However, the availability of human-derived tau is extremely limited. Generation of tau variants that can mimic the pathogenicity of human-derived tau seeds would significantly extend the scale of experimental design within the field of tauopathy research. Previous studies have demonstrated that in vitro seeding reactions can amplify the beta-sheet structure of tau protein from a minute quantity of human-derived tau. However, whether the strain-specific pathogenicities of the original, human-derived tau seeds are conserved in the amplified tau strains has yet to be experimentally validated. Here, we used biochemically enriched brain-derived tau seeds from Alzheimer’s disease (AD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) patient brains with a modified seeding protocol to template the recruitment of recombinant 2N4R (T40) tau in vitro. We quantitatively interrogated efficacy of the amplification reactions and the pathogenic fidelity of the amplified material to the original tau seeds using recently developed sporadic tau spreading models. Our data suggest that different tau strains can be faithfully amplified in vitro from tau isolated from different tauopathy brains and that the amplified tau variants retain their strain-dependent pathogenic characteristics. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-020-02253-4. |
Databáze: | OpenAIRE |
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