This is a summary of de Weerd, L., Hummel, S., Müller, S.A. et al. Early intervention anti-Aβ immunotherapy attenuates microglial activation without inducing exhaustion at residual plaques. Published in Molecular Neurodegeneration 20, 92 (2025). https://doi.org/10.1186/s13024-025-00878-1
The challenge
The build-up of amyloid β-peptide (Aβ) in the brain starts as early as twenty-five years before clinical symptoms appear. It triggers a cascade of Tau aggregation, neurodegeneration, and neuroinflammation – ultimately leading to cognitive decline. Anti-Aβ immunotherapy is currently the only disease-modifying treatment for patients and requires long-term treatment over the course of months or years. Microglia are the main effectors of immunotherapy in the brain by removing amyloid plaques. However, little is known how these cells are affected by long-term treatment and if they remain functional after they performed their job and returned to a resting state. To enhance the safety and efficacy of chronic immunotherapy, it is essential to understand the effects on immune cell function. We therefore investigated the effects of long-term chronic anti-Aβ treatment on amyloid plaque pathology and microglial response.
Our approach
We used a mouse model that forms amyloid plaques and treated mice using an early intervention paradigm with an anti-Aβ antibody for 16 weeks. We further relied on bulk RNA sequencing and in vivo PET-imaging, together with proteomic analyses of cerebrospinal fluid (CSF).
Our findings
We found that after 16 weeks of treatment with an anti-Aβ antibody, aggregated Aβ as well as amyloid plaques were reduced in a dose-dependent manner. We also found brain-wide less disease-associated microglial activation, which correlated with the reduction in plaque load and was confirmed in CSF and by PET. However, we also found that microglial activation around residual plaques remained high, with these cells showing a unique antibody-driven microglial phenotype, indicative of an ongoing treatment response.
The implications
Our findings emphasize the importance of early intervention with anti-Aβ antibodies and show that microglia remain engaged with residual plaques even after long-term chronic treatment. This supports the chronic use of anti-Aβ immunotherapy and the therapeutic potential of combining this treatment with strategies that enhance microglial function to improve long-term outcomes in Alzheimer's disease.
Creating SyNergies
The study was led by Christian Haass and Lis de Weerd, and included our members Stefan Lichtenthaler and Matthias Brendel. Our project made intensive use of two SyNergy’s technology hubs: PET-imaging (led by Matthias Brendel) and proteomics (led by Stefan Lichtenthaler) were of central importance for our project.
