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

Patricia Yuste-Checa, Victoria A. Trinkaus, Irene Riera-Tur, Rahmi Imamoglu, Theresa F. Schaller, Huping Wang, Irina Dudanova, Mark S. Hipp, Andreas Bracher and F. Ulrich Hartl ()
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Patricia Yuste-Checa: Max Planck Institute of Biochemistry
Victoria A. Trinkaus: Max Planck Institute of Biochemistry
Irene Riera-Tur: Max Planck Institute of Neurobiology
Rahmi Imamoglu: Max Planck Institute of Biochemistry
Theresa F. Schaller: Max Planck Institute of Biochemistry
Huping Wang: Max Planck Institute of Biochemistry
Irina Dudanova: Max Planck Institute of Neurobiology
Mark S. Hipp: Max Planck Institute of Biochemistry
Andreas Bracher: Max Planck Institute of Biochemistry
F. Ulrich Hartl: Max Planck Institute of Biochemistry

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25060-1

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