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.
Highlights
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
We measured aggregate seeding with TauRD-YT cells, a human embryonic kidney 293T (HEK293T) cell line stably coexpressing the repeat domain of Tau (TauRD; residues 244-372 with frontotemporal dementia (FTD) mutations P301L/V337M) fused to YFP or mTurquoise[2], whose co-aggregation during fibril formation results in fluorescence resonance energy transfer (FRET)[41] (Fig. 1a)
Mutation of the two cysteines in TauRD avoids the formation of intramolecular disulfide bonds that slows fibril formation[42]
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. Given the predominant role of extracellular Clu as the chaperone active form, it remains to be understood whether Clu modulates transcellular Tau seeding and influences overall pathology. Our results show that Clu can strongly enhance Tau aggregate propagation by binding and stabilizing seeding active Tau species for cellular uptake. Upregulation of Clu in AD has the potential to accelerate disease progression by enhancing the seeding competence of Tau aggregates
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