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LRP1 is a master regulator of tau uptake and spread
Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, Leshuk C, Hernandez I et al.. Nature, 2020-04-01
Topic: Brain proteins, microglia and lab models
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 encephalopathy 1 . Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity 2 . This observation and complementary experimental studies 3,4 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.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Rauch, J. N., Luna, G., Guzman, E., Audouard, M., Challis, C., Sibih, Y. E., et al. (2020). LRP1 is a master regulator of tau uptake and spread. Nature. https://doi.org/10.1038/s41586-020-2156-5
Vancouver
Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, et al. LRP1 is a master regulator of tau uptake and spread. Nature. 2020. doi:10.1038/s41586-020-2156-5. PMID: 32296178.
BibTeX
@article{rauch2020-32296178,
author = {Rauch, J. N. and Luna, G. and Guzman, E. and Audouard, M. and Challis, C. and Sibih, Y. E. and Leshuk, C. and Hernandez, I. and others},
title = {{LRP1 is a master regulator of tau uptake and spread}},
journal = {Nature},
year = {2020},
doi = {10.1038/s41586-020-2156-5},
pmid = {32296178},
url = {https://doi.org/10.1038/s41586-020-2156-5}
}
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Key findings
- This observation and complementary experimental studies 3,4 have suggested that tau can spread in a prion-like manner, by passing to naive cells in which it templates misfolding and aggregation.
- Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived 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.
Why it matters
In cells and a mouse model, reducing LRP1 lowered tau uptake and spread between neurons, identifying LRP1 as a possible target for diseases involving tau spread. This is laboratory and animal work and does not yet show benefit in people.
Study details
- Evidence strengthLow
How this study scored 63/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature) |
| Journal's citation record | 4 / 4 | Nature: journal h-index 1,841 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2020 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 543 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 67.9 citations a year over 8 year(s) since 2020 |
| Impact for its field and year | 5 / 6 | Cited 39.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 15 other studies in this library |
| Still being cited | 4 / 4 | Cited 234 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Kenneth S. Kosik: h-index 108 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 32296178) |
| Free to read | 2 / 2 | Free to read |
| Total | 63 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41586-020-2156-5
- PubMed: 32296178
- Original source →
- Free full text: eScholarship (California Digital Library) →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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