Tau in the brain interstitial fluid is fragmented and seeding–competent
| Autor: | Florie LePrieult, Ina Mairhofer, Karen Bodie, Jonas Hoppe, Marcus W. Meinhardt, Sonja Julier, Gudrun Plotzky, Ebru Ercan-Herbst, Yulia Mordashova, Sandra Biesinger, Miroslav Cik, Kerstin Schlegel, Dagmar E. Ehrnhoefer, Laura Gasparini, Esther Rodriguez-Correa, Mario Mezler, Corinna Klein, Andreas Striebinger, Erica Barini |
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| Rok vydání: | 2022 |
| Předmět: |
Genetically modified mouse
Aging Microdialysis Transgene Tau protein Mice Transgenic tau Proteins Protein Aggregation Pathological In vivo Interstitial fluid mental disorders medicine Animals Humans Phosphorylation biology Chemistry General Neuroscience Brain Extracellular Fluid medicine.disease Peptide Fragments Cell biology Disease Models Animal HEK293 Cells Tauopathies biology.protein Neurology (clinical) Tauopathy Geriatrics and Gerontology Alzheimer's disease Developmental Biology |
| Zdroj: | Neurobiology of Aging |
| ISSN: | 0197-4580 |
| Popis: | In Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that in Tau transgenic mice, human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells. Notably, immunodepletion of ISF phosphorylated Tau, but not Tau fragments, significantly reduces its ability to seed Tau aggregation and only a fraction of Tau, separated by ultracentrifugation, is seeding competent. These results indicate that ISF seeding competence is driven by a small subset of Tau, which potentially contribute to the propagation of Tau pathology.HighlightsIn interstitial fluid (ISF) of transgenic mice, Tau comprises >10 distinct fragmentsISF Tau decreases with Tauopathy progression, while its phosphorylation increasesOnly ISF from mice with established Tauopathy is seeding competent in vitroRemoval of phospho-Tau reduces ISF seeding competenceISF seeding competence is driven by less soluble, aggregated and phosphorylated TauGraphical abstract |
| Databáze: | OpenAIRE |
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