期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 23, 页码 19440-19451出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.346072
关键词
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资金
- National Institutes of Health (NIH), NINDS [P50AG005681, 1R01NS071835-01]
- NIH Neuroscience Blueprint Interdisciplinary Center [P30 (NS057105)]
- Muscular Dystrophy Association
- American Health Assistance Foundation
- Ruth K. Broad Foundation
- Tau Consortium
- Hope Center for Neurological Disorders at Washington University in St. Louis
- Donald H. and Mary Jane Buchanan Foundation
- Barnes-Jewish Hospital Foundation
- Siteman Cancer Center of Washington University in St. Louis
- Bakewell Neuroimaging Core
- Alafi Neuroimaging Laboratory
- Bakewell Family Foundation
Aggregation of the microtubule associated protein Tau is associated with several neurodegenerative disorders, including Alzheimer disease and frontotemporal dementia. In Alzheimer disease, Tau pathology spreads progressively throughout the brain, possibly along existing neural networks. However, it is still unclear how the propagation of Tau misfolding occurs. Intriguingly, in animal models, vaccine-based therapies have reduced Tau and synuclein pathology by uncertain mechanisms, given that these proteins are intracellular. We have previously speculated that trans-cellular propagation of misfolding could be mediated by a process similar to prion pathogenesis, in which fibrillar Tau aggregates spread pathology from cell to cell. However, there has been little evidence to demonstrate true trans-cellular propagation of Tau misfolding, in which Tau aggregates from one cell directly contact Tau protein in the recipient cell to trigger further aggregation. Here we have observed that intracellular Tau fibrils are directly released into the medium and then taken up by co-cultured cells. Internalized Tau aggregates induce fibrillization of intracellular Tau in these naive recipient cells via direct protein-protein contact that we demonstrate using FRET. Tau aggregation can be amplified across several generations of cells. An anti-Tau monoclonal antibody blocks Tau aggregate propagation by trapping fibrils in the extracellular space and preventing their uptake. Thus, propagation of Tau protein misfolding among cells can be mediated by release and subsequent uptake of fibrils that directly contact native protein in recipient cells. These results support the model of aggregate propagation by templated conformational change and suggest a mechanism for vaccine-based therapies in neurodegenerative diseases.
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