Authors
Maria Kreger Karabova, Anna Del Ser-Badia, Anne Hedegaard, Sam J Washer, Zeynep Baykam, Darragh P O'Brien, Iolanda Vendrell, Svenja S Hester, Roman Fischer, Errin Johnson, Charlotte E Melia, Teige R S Matthews-Palmer, Rishi Matadeen, Alessia Santambrogio, Michael A Metrick, Michele Vendruscolo, Sophie Keeling, Kimberly Ai Xian Cheam, William A McEwan, Kenneth S Kosik, Theresa A Day, William S James, Sally A Cowley
Published in
Alzheimer's & dementia : the journal of the Alzheimer's Association. Volume 22. Issue 4. Pages e71337.
Abstract
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.
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.
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.
Our study reveals new insights into human microglial responses to tau, highlighting opportunities to limit pathogenic tau spread.
PMID:
41943483
Bibliographic data and abstract were imported from PubMed on 15 Sep 2026.
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