Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease
Alzheimer's disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. We compare actively immunized patients with AD with nonimmunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aβ removal after lecanemab treatment. We uncover spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of the triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) in microglia across immunization approaches, which correlate positively with antibody responses and Aβ removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aβ clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aβ removal and shed light on the role of microglia in immune-mediated Aβ clearance. Importantly, our work uncovers potential molecular targets that could enhance Aβ-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD.
Authors
- Joshua Kuruvilla
- Rudolph J. Castellani (ORCID: https://orcid.org/0000-0002-5414-3184)
- Ann Forsyth (ORCID: https://orcid.org/0000-0002-8400-6842)
- Delphine Boche (ORCID: https://orcid.org/0000-0002-5884-130X)
- Robert Vassar (ORCID: https://orcid.org/0000-0002-1358-504X)
- Talia Krainc (ORCID: https://orcid.org/0000-0001-5665-241X)
- Thomas H. Watson
- Nate Shepard
- Lily Camp (ORCID: https://orcid.org/0009-0002-3032-2791)
- Benney MR Argue (ORCID: https://orcid.org/0009-0009-9799-901X)
- David Gate (ORCID: https://orcid.org/0000-0003-0481-9657)
- Pouya Jamshidi (ORCID: https://orcid.org/0000-0002-2038-8589)
- Jeanette L. Norman
- Alex J. Edwards
- Joshua Cahan (ORCID: https://orcid.org/0000-0002-9453-733X)
- Brooke Simonton (ORCID: https://orcid.org/0000-0002-1366-1268)
- James A. R. Nicoll (ORCID: https://orcid.org/0000-0002-9444-7246)
- Jake Boles (ORCID: https://orcid.org/0000-0001-5501-2162)
- Lynn van Olst (ORCID: https://orcid.org/0000-0001-7569-0470)
- Ziyang Zhang (ORCID: https://orcid.org/0000-0001-5870-704X)
- Hang Xu (ORCID: https://orcid.org/0000-0002-8336-4445)
- Mengwei Li (ORCID: https://orcid.org/0000-0001-6163-2827)
- Jinmiao Chen (ORCID: https://orcid.org/0000-0001-7547-6423)
Institutions
- Northwestern University (US)
- Agency for Science, Technology and Research (SG)
- National University of Singapore (SG)
- University Hospital Southampton NHS Foundation Trust (GB)
- Duke-NUS Medical School (SG)
- Bioinformatics Institute (SG)
- University of Southampton (GB)
Publication Details
- Journal
- Nature Medicine
- Published
- 2025-03-06
- DOI
- https://doi.org/10.1038/s41591-025-03574-1
- Citations
- 78
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 65.70
Funders
- Alzheimer's Association
- BrightFocus Foundation
- Alzheimer Nederland
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke