Tau uptake by human neurons depends on receptor LRP1 and kinase LRRK2

Extracellular release and uptake of pathogenic forms of the microtubule-associated protein tau contribute to the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease. Defining the cellular mechanisms and pathways for tau entry to human neurons is essential to understanding tauopathy pathogenesis and enabling the rational design of disease-modifying therapeutics. Here, whole-genome, loss-of-function CRISPR screens in human iPSC-derived excitatory neurons, the major neuronal cell type affected in these diseases, provide insights into the different cellular pathways for uptake of extracellular monomeric and fibrillar tau. Monomeric and fibrillar tau are both taken up by human neurons by receptor-mediated endocytosis, but involve different routes of entry at the neuronal surface: the low-density lipoprotein LRP1 is the primary receptor for monomeric tau, but contributes less to fibrillar tau entry. Similarly, endocytosis of monomeric tau is dependent on the familial Parkinson's disease gene LRRK2, but not required for endocytosis of fibrillar tau. These findings implicate LRP1 and LRRK2 in the pathogenesis of tauopathies and Parkinson's disease, and identify LRRK2 as a potential therapeutic target for altering progression of these diseases.

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Publication Details

Journal
The EMBO Journal
Published
2025-08-11
DOI
https://doi.org/10.1038/s44318-025-00514-0
Citations
3
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
3.49

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article

Tau uptake by human neurons depends on receptor LRP1 and kinase LRRK2

Ashley Campbell, Andrew Bassett, Alessio Strano, Emre Karakoç et al.
3 citations
The EMBO Journal
Alzheimer's disease research and treatments
3.49
article

Tau uptake by human neurons depends on receptor LRP1 and kinase LRRK2

Ashley Campbell, Andrew Bassett, Alessio Strano, Emre Karakoç, Bernardino Ghetti, Christy Hung, Tiana S. Behr, James Smith, Eleanor J. Tuck, Rick Livesey, Alastair D. Reith, Lewis Evans, Francesco Iorio, Benjamin Falcon
article en
3 citations

Abstract

Extracellular release and uptake of pathogenic forms of the microtubule-associated protein tau contribute to the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease. Defining the cellular mechanisms and pathways for tau entry to human neurons is essential to understanding tauopathy pathogenesis and enabling the rational design of disease-modifying therapeutics. Here, whole-genome, loss-of-function CRISPR screens in human iPSC-derived excitatory neurons, the major neuronal cell type affected in these diseases, provide insights into the different cellular pathways for uptake of extracellular monomeric and fibrillar tau. Monomeric and fibrillar tau are both taken up by human neurons by receptor-mediated endocytosis, but involve different routes of entry at the neuronal surface: the low-density lipoprotein LRP1 is the primary receptor for monomeric tau, but contributes less to fibrillar tau entry. Similarly, endocytosis of monomeric tau is dependent on the familial Parkinson's disease gene LRRK2, but not required for endocytosis of fibrillar tau. These findings implicate LRP1 and LRRK2 in the pathogenesis of tauopathies and Parkinson's disease, and identify LRRK2 as a potential therapeutic target for altering progression of these diseases.

The EMBO JournalVol. 44(18)
Talisman Energy (GB), City University of Hong Kong (HK), MRC Laboratory of Molecular Biology (GB), GlaxoSmithKline (United Kingdom) (GB), Great Ormond Street Hospital (GB), Wellcome Sanger Institute (GB), ETH Zurich (CH), Open Targets (GB), Mission Therapeutics (United Kingdom) (GB), Human Technopole (IT), Institute of Child Health (IN), Indiana University School of Medicine, University College London (GB), Indiana University – Purdue University Indianapolis (US)
Biogen, Wellcome Trust, Stem Cell Network, National Institute for Health and Care Research, University of Oxford, Great Ormond Street Hospital Charity, Alzheimer’s Research UK, Dementias Platform UK, NIHR Great Ormond Street Hospital Biomedical Research Centre
Good health and well-being
Openalex Percentile: Top 7%
Alzheimer's disease research and treatments
3.49
DOIOpen Access PDFOpenAlex
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