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Sensitive Detection of Proteopathic Seeding Activity with FRET Flow Cytometry
Published on: December 8, 2015
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Tau in the brain interstitial fluid is fragmented and seeding-competent
Erica Barini1, Gudrun Plotzky1, Yulia Mordashova2
1AbbVie Deutschland GmbH & Co. KG , Neuroscience Discovery, Knollstrasse, Ludwigshafen, Germany.
Neurobiology of Aging
|October 16, 2021
Summary
Researchers discovered that truncated Tau fragments in brain fluid during Alzheimer's disease progression are linked to Tau pathology spread. Phosphorylated Tau fragments in the interstitial fluid are key drivers of Tau aggregation.
Area of Science:
- Neuroscience
- Biochemistry
Background:
- Tau pathology is a hallmark of Alzheimer's disease (AD), believed to spread between connected brain regions.
- The specific forms and pathological significance of Tau released into the brain interstitial fluid (ISF) during Tauopathy development are not well understood.
Purpose of the Study:
- To characterize the forms of human Tau (hTau) present in the ISF in vivo during Tauopathy.
- To investigate the pathological relevance and seeding potential of ISF Tau in a mouse model of Tauopathy.
Main Methods:
- In vivo microdialysis was employed to collect ISF from Tau transgenic mice.
- Biochemical analyses, including fragmentation pattern analysis and ultracentrifugation, were performed on collected ISF.
- HEK293-Tau biosensor cells were used to assess the Tau aggregation-seeding capacity of ISF.
Main Results:
- ISF hTau in transgenic mice consists of at least 10 distinct truncated fragments, with a consistent fragmentation pattern across models and stages.
- ISF Tau concentration decreased with Tauopathy progression, while its phosphorylation level increased.
- ISF from mice with Tauopathy induced Tau aggregation in biosensor cells; immunodepletion of phosphorylated Tau significantly reduced this seeding ability.
Conclusions:
- The study identifies truncated and phosphorylated Tau fragments in ISF as key players in Tau pathology propagation.
- A small subset of Tau, particularly phosphorylated forms, possesses seeding competence and may drive cell-to-cell spread of Tau pathology in Alzheimer's disease.
