Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 2, Pages 956-967Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.515445
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Funding
- Wellcome Trust [089703/Z/09/Z]
- Medical Research Council [089703/Z/09/Z, MR/K015850/1, G09022243]
- Alzheimer's Research UK [ARUK-EG2012A-1, ARUK-ESG2012-1]
- Engineering and Physical Sciences Research Council [EP/H018301/1]
- European Research Council [AdG 233232]
- EPSRC [EP/H018301/1] Funding Source: UKRI
- MRC [MR/K015850/1, MC_G1000734, G0902243, MR/K02292X/1] Funding Source: UKRI
- Alzheimers Research UK [ARUK-EG2012A-1, ARUK-ESG2012-1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/H018301/1] Funding Source: researchfish
- Medical Research Council [G0902243, MC_G1000734, MR/K02292X/1, MR/K015850/1] Funding Source: researchfish
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Understanding the formation and propagation of aggregates of the Alzheimer disease-associated Tau protein in vivo is vital for the development of therapeutics for this devastating disorder. Using our recently developed live-cell aggregation sensor in neuron-like cells, we demonstrate that different variants of exogenous monomeric Tau, namely full-length Tau (hTau40) and the Tau-derived construct K18 comprising the repeat domain, initially accumulate in endosomal compartments, where they form fibrillar seeds that subsequently induce the aggregation of endogenous Tau. Using superresolution imaging, we confirm that fibrils consisting of endogenous and exogenous Tau are released from cells and demonstrate their potential to spread Tau pathology. Our data indicate a greater pathological risk and potential toxicity than hitherto suspected for extracellular soluble Tau.
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