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000151529 0247_ $$2doi$$a10.1038/s41586-020-2156-5
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000151529 0247_ $$2ISSN$$a1476-4687
000151529 0247_ $$2ISSN$$a2058-1106
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000151529 037__ $$aDZNE-2020-01113
000151529 041__ $$aEnglish
000151529 082__ $$a530
000151529 1001_ $$aRauch, Jennifer N.$$b0
000151529 245__ $$aLRP1 is a master regulator of tau uptake and spread
000151529 260__ $$aLondon$$bMacmillan28177$$c2020
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000151529 520__ $$aThe spread of protein aggregates during disease progression is a common theme underlying many neurodegenerative diseases. The microtubule-associated protein tau has a central role in the pathogenesis of several forms of dementia known as tauopathies—including Alzheimer’s disease, frontotemporal dementia and chronic traumatic encephalopathy1. Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity2. This observation and complementary experimental studies3,4 have suggested that tau can spread in a prion-like manner, by passing to naive cells in which it templates misfolding and aggregation. However, although the propagation of tau has been extensively studied, the underlying cellular mechanisms remain poorly understood. Here we show that the low-density lipoprotein receptor-related protein 1 (LRP1) controls the endocytosis of tau and its subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule-binding repeat region of tau. Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons. Our results identify LRP1 as a key regulator of tau spread in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.
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000151529 650_2 $$2MeSH$$aAnimals
000151529 650_2 $$2MeSH$$aCell Line
000151529 650_2 $$2MeSH$$aEndocytosis
000151529 650_2 $$2MeSH$$aFemale
000151529 650_2 $$2MeSH$$aHumans
000151529 650_2 $$2MeSH$$aLigands
000151529 650_2 $$2MeSH$$aLow Density Lipoprotein Receptor-Related Protein-1: genetics
000151529 650_2 $$2MeSH$$aLow Density Lipoprotein Receptor-Related Protein-1: metabolism
000151529 650_2 $$2MeSH$$aMale
000151529 650_2 $$2MeSH$$aMice
000151529 650_2 $$2MeSH$$aNeurons: metabolism
000151529 650_2 $$2MeSH$$atau Proteins: metabolism
000151529 7001_ $$aLuna, Gabriel$$b1
000151529 7001_ $$aGuzman, Elmer$$b2
000151529 7001_ $$aAudouard, Morgane$$b3
000151529 7001_ $$aChallis, Collin$$b4
000151529 7001_ $$00000-0002-0839-5428$$aSibih, Youssef E.$$b5
000151529 7001_ $$aLeshuk, Carolina$$b6
000151529 7001_ $$aHernandez, Israel$$b7
000151529 7001_ $$0P:(DE-2719)2812695$$aWegmann, Susanne$$b8$$udzne
000151529 7001_ $$00000-0002-7959-9401$$aHyman, Bradley T.$$b9
000151529 7001_ $$00000-0001-5868-348X$$aGradinaru, Viviana$$b10
000151529 7001_ $$00000-0002-3819-7019$$aKampmann, Martin$$b11
000151529 7001_ $$0P:(DE-HGF)0$$aKosik, Kenneth S.$$b12$$eCorresponding author
000151529 77318 $$2Crossref$$3journal-article$$a10.1038/s41586-020-2156-5$$b : Springer Science and Business Media LLC, 2020-04-01$$n7803$$p381-385$$tNature$$v580$$x0028-0836$$y2020
000151529 773__ $$0PERI:(DE-600)2590711-6$$a10.1038/s41586-020-2156-5$$gVol. 580, no. 7803, p. 381 - 385$$n7803$$p381-385$$tNature <London> / Physical science$$v580$$x0028-0836$$y2020
000151529 8564_ $$uhttps://www.nature.com/articles/s41586-020-2156-5
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