Tracking tau and cellular responses in human iPSC‐microglia: from uptake to seedable secretion, including in extracellular vesicles
INTRODUCTION: Microglia have been implicated in the templated spread of tau aggregates in tauopathies through mouse studies. However, it is unclear whether these findings translate to human disease. METHODS: We challenged human induced pluripotent stem cell (iPSC)-derived microglia-like-cells (iMGL) with monomeric and fibrillar recombinant tau and tau purified from Alzheimer's patient brains, examining in detail the uptake, processing, release, and seeding of tau by microglia. RESULTS: iMGL take up tau via lipoprotein receptor-related protein 1 (LRP)1 and heparan sulfate proteoglycans, with leucine-rich repeat kinase 2 affecting LRP1 trafficking. Monomeric tau is digested effectively with minimal effects on iMGL, but recombinant or brain-derived tau fibrils induce chemokine/interferon response subtypes, alongside downregulation of homeostatic genes. Fibrillar tau is degradation-resistant, can escape into the cytoplasm, and becomes phosphorylated on two specific residues. iMGL release partially digested fibrillar tau, including in extracellular vesicles, visualized by cryo-electron microscopy, that seed aggregation in neurons. DISCUSSION: Our study reveals new insights into human microglial responses to tau, highlighting opportunities to limit pathogenic tau spread.
Authors
- William James (ORCID: https://orcid.org/0000-0002-2506-1198)
- Charlotte E. Melia
- Theresa A. Day
- Michael A. Metrick (ORCID: https://orcid.org/0000-0002-9998-4630)
- Iolanda Vendrell (ORCID: https://orcid.org/0000-0001-7187-4061)
- Maria Kreger Karabova (ORCID: https://orcid.org/0000-0003-1742-0151)
- Roman Fischer (ORCID: https://orcid.org/0000-0001-7927-604X)
- Rishi Matadeen
- Sophie Keeling (ORCID: https://orcid.org/0000-0002-6413-2550)
- Svenja Hester (ORCID: https://orcid.org/0000-0003-0744-5216)
- Anna del Ser‐Badia (ORCID: https://orcid.org/0000-0003-1142-1989)
- Sam Washer (ORCID: https://orcid.org/0000-0003-4004-8984)
- Sally A. Cowley (ORCID: https://orcid.org/0000-0003-0297-6675)
- William A. McEwan (ORCID: https://orcid.org/0000-0002-4408-0407)
- Errin Johnson (ORCID: https://orcid.org/0000-0001-8435-9472)
- Anne Hedegaard (ORCID: https://orcid.org/0000-0003-1536-896X)
- Kimberly Ai Xian Cheam
- Zeynep Baykam
- Michele Vendruscolo
- Darragh O'Brien
- Teige R. S. Matthews‐Palmer
- Alessia Santambrogio
- Kenneth S. Kosik
Institutions
- Institute of Cancer Research (GB)
- University of California, Santa Barbara (US)
- Eli Lilly (United States) (US)
- University of Cambridge (GB)
- University of Oxford (GB)
- Wellcome Centre for Integrative Neuroimaging (GB)
- UK Dementia Research Institute (GB)
- Science Oxford (GB)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1002/alz.71337
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Eli Lilly and Company
- Alzheimer's Society
- King's College London