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

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 naïve cells and induce the prion-like templ...

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Bibliographic Details
Published in:Nature communications 2021-08, Vol.12 (1), p.4863-4863, Article 4863
Main Authors: Yuste-Checa, Patricia, Trinkaus, Victoria A., Riera-Tur, Irene, Imamoglu, Rahmi, Schaller, Theresa F., Wang, Huping, Dudanova, Irina, Hipp, Mark S., Bracher, Andreas, Hartl, F. Ulrich
Format: Article
Language:English
Subjects:
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Agglomeration
Aggregates
Alzheimer's disease
Clusterin
Cytosol
Dementia disorders
Endocytosis
Frontotemporal dementia
Humanities and Social Sciences
multidisciplinary
Neurodegeneration
Neurodegenerative diseases
Neurotoxicity
Pathology
Science
Science (multidisciplinary)
Seeds
Tau protein
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Summary: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 naïve 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. 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.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-25060-1