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  The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

Yuste-Checa, P., Trinkaus, V. A., Riera-Tur, I., Imamoglu, R., Schaller, T. F., Wang, H., et al. (2021). The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model. Nature Communications, 12(1): 4863. doi:10.1038/s41467-021-25060-1.

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 Creators:
Yuste-Checa, Patricia1, Author              
Trinkaus, Victoria A.1, Author              
Riera-Tur, Irene2, Author
Imamoglu, Rahmi1, Author              
Schaller, Theresa F.2, Author
Wang, Huping1, Author
Dudanova, Irina2, Author
Hipp, Mark S.1, Author              
Bracher, Andreas1, Author              
Hartl, F. Ulrich1, Author
Affiliations:
1Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              
2external, ou_persistent22              

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Free keywords: GENOME-WIDE ASSOCIATION; ALZHEIMERS-DISEASE; ALPHA-SYNUCLEIN; AMYLOID-BETA; MOUSE MODEL; CEREBROSPINAL-FLUID; IDENTIFIES VARIANTS; PLASMA CLUSTERIN; APOLIPOPROTEIN-E; MECHANISMScience & Technology - Other Topics;
 Abstract: Variants of the extracellular chaperone Clusterin are associated with Alzheimer's disease (AD) and Clusterin levels are elevated in AD patient brains. Here, the authors show that Clusterin binds to oligomeric Tau, which enhances the seeding capacity of Tau aggregates upon cellular uptake. They also demonstrate that Tau/Clusterin complexes enter cells via the endosomal pathway, resulting in damage to endolysosomes and entry into the cytosol, where they induce the aggregation of endogenous, soluble Tau. Spreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimer's disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naive cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.

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Language(s): eng - English
 Dates: 2021
 Publication Status: Published online
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Degree: -

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 12 (1) Sequence Number: 4863 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723