LRP1 is a master regulator of tau uptake and spread
Copyright policy )LRP1 is a master regulator of tau uptake and spread
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.
- University of California, Berkeley United States
- University of California System United States
- QB3 United States
- Massachusetts General Hospital United States
- UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Male, Aging, metabolism [Low Density Lipoprotein Receptor-Related Protein-1], Ligands (mesh), General Science & Technology (science-metrix), Neurodegenerative, Acquired Cognitive Impairment (rcdc), Alzheimer's Disease, Ligands, Aging (rcdc), Mice, Brain Disorders (rcdc), Dementia (rcdc), 2.1 Biological and endogenous factors, Animals (mesh), Aetiology, Male (mesh), Alzheimer's Disease Related Dementias (ADRD), Neurosciences (rcdc), Neurodegenerative (rcdc), Neurons, Humans (mesh), Alzheimer's Disease (rcdc), Mice (mesh), Biological Sciences, Endocytosis, Alzheimer's Disease Related Dementias (ADRD) (rcdc), Frontotemporal Dementia (FTD), Frontotemporal Dementia (FTD) (rcdc), metabolism [Neurons], Neurological, Low Density Lipoprotein Receptor-Related Protein-1 (mesh), Female, Low Density Lipoprotein Receptor-Related Protein-1, General Science & Technology, genetics [Low Density Lipoprotein Receptor-Related Protein-1], 610, tau Proteins, Article, Cell Line, Acquired Cognitive Impairment, Endocytosis (mesh), Animals, Humans, 31 Biological Sciences (for-2020), Neurons (mesh), Neurological (hrcs-hc), Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors (hrcs-rac), metabolism [tau Proteins], Brain Disorders, 3101 Biochemistry and Cell Biology (for-2020), Emerging Infectious Diseases, Female (mesh), Cell Line (mesh), Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) (rcdc), Biochemistry and Cell Biology, tau Proteins (mesh), ddc: ddc:530
Male, Aging, metabolism [Low Density Lipoprotein Receptor-Related Protein-1], Ligands (mesh), General Science & Technology (science-metrix), Neurodegenerative, Acquired Cognitive Impairment (rcdc), Alzheimer's Disease, Ligands, Aging (rcdc), Mice, Brain Disorders (rcdc), Dementia (rcdc), 2.1 Biological and endogenous factors, Animals (mesh), Aetiology, Male (mesh), Alzheimer's Disease Related Dementias (ADRD), Neurosciences (rcdc), Neurodegenerative (rcdc), Neurons, Humans (mesh), Alzheimer's Disease (rcdc), Mice (mesh), Biological Sciences, Endocytosis, Alzheimer's Disease Related Dementias (ADRD) (rcdc), Frontotemporal Dementia (FTD), Frontotemporal Dementia (FTD) (rcdc), metabolism [Neurons], Neurological, Low Density Lipoprotein Receptor-Related Protein-1 (mesh), Female, Low Density Lipoprotein Receptor-Related Protein-1, General Science & Technology, genetics [Low Density Lipoprotein Receptor-Related Protein-1], 610, tau Proteins, Article, Cell Line, Acquired Cognitive Impairment, Endocytosis (mesh), Animals, Humans, 31 Biological Sciences (for-2020), Neurons (mesh), Neurological (hrcs-hc), Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors (hrcs-rac), metabolism [tau Proteins], Brain Disorders, 3101 Biochemistry and Cell Biology (for-2020), Emerging Infectious Diseases, Female (mesh), Cell Line (mesh), Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) (rcdc), Biochemistry and Cell Biology, tau Proteins (mesh), ddc: ddc:530
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