The Alzheimer’s therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia
Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer's disease.
Authors
- Tom Jaspers (ORCID: https://orcid.org/0000-0002-7485-4397)
- Kristofer Davie (ORCID: https://orcid.org/0000-0003-2182-1249)
- Giulia Albertini (ORCID: https://orcid.org/0000-0002-8215-2432)
- Bart De Strooper (ORCID: https://orcid.org/0000-0001-5455-5819)
- Marie‐Lynn Cuypers (ORCID: https://orcid.org/0000-0001-7540-389X)
- Lutgarde Serneels (ORCID: https://orcid.org/0000-0002-5463-4231)
- Maarten Dewilde (ORCID: https://orcid.org/0000-0002-3138-281X)
- Leen Wolfs (ORCID: https://orcid.org/0009-0003-5193-6722)
- Mark Fiers (ORCID: https://orcid.org/0000-0001-5694-2409)
- Marta Wojno (ORCID: https://orcid.org/0000-0003-2711-1264)
- Emanuela Pasciuto (ORCID: https://orcid.org/0000-0002-5391-9585)
- Katrien Horré (ORCID: https://orcid.org/0000-0002-6801-3137)
- Magdalena Zielonka (ORCID: https://orcid.org/0000-0001-9641-9778)
- Suresh Poovathingal (ORCID: https://orcid.org/0000-0002-3236-2255)
- Katleen Craessaerts (ORCID: https://orcid.org/0000-0001-6684-8475)
- Veerle van Lieshout (ORCID: https://orcid.org/0000-0003-4033-4286)
- An Snellinx
- Ciana Xu (ORCID: https://orcid.org/0009-0009-8280-1736)
Institutions
- Allen Institute for Brain Science (US)
- University of Antwerp (BE)
- Vlaams Instituut voor Biotechnologie (BE)
- Center for Human Genetics (US)
- UK Dementia Research Institute (GB)
- VIB-UAntwerp Center for Molecular Neurology (BE)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- University College London (GB)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1038/s41593-025-02125-8
- Citations
- 5
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 5.82