Journal Article

DZNE-2020-01113

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png LRP1 is a master regulator of tau uptake and spread

Rauch, J. N. ; Luna, G. ; Guzman, E. ; Audouard, M. ; Challis, C. ; Sibih, Y. E. ; Leshuk, C. ; Hernandez, I. ; Wegmann, S.DZNE* ; Hyman, B. T. ; Gradinaru, V. ; Kampmann, M. ; Kosik, K. S. (Corresponding author)

2020
Macmillan28177 London

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Please use a persistent id in citations: doi:10.1038/s41586-020-2156-5

Abstract: The 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.

Keyword(s): Animals (MeSH) ; Cell Line (MeSH) ; Endocytosis (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Ligands (MeSH) ; Low Density Lipoprotein Receptor-Related Protein-1: genetics (MeSH) ; Low Density Lipoprotein Receptor-Related Protein-1: metabolism (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Neurons: metabolism (MeSH) ; tau Proteins: metabolism (MeSH)

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Contributing Institute(s):

1. Protein Actions in Neurodegeneration (AG Wegmann)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2020

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; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 40 ; Index Chemicus ; JCR ; SCOPUS ; Web of Science Core Collection ; Zoological Record

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