Early intervention anti-Aβ immunotherapy attenuates microglial activation without inducing exhaustion at residual plaques

作者：Lis de Weerd, Selina Hummel, Stephan A. Müller, Iñaki Paris, Thomas Sandmann, Marie Eichholtz, Robin Gröger, Amelie L. Englert, Stephan Wagner, Connie Ha, Sonnet S. Davis, Valerie Warkins, Dan Xia, Brigitte Nuscher, Anna Berghofer, Marvin Reich, Astrid Feiten, Kai Schlepckow, Michael Willem, Stefan F. Lichtenthaler, Joseph W. Lewcock, Kathryn M. Monroe, Matthias Brendel, Christian Haass · 发表于：Molecular Neurodegeneration · 年份：2025 · DOI：10.1186/s13024-025-00878-1 · 被引用次数：10 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Alzheimer's disease research and treatments、Tryptophan and brain disorders

Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer's disease. Efficient amyloid clearance has been proven in clinical trials testing anti-Aβ antibodies, by their impact on cognitive endpoints correlating with the extent of amyloid removal. However, treatment is associated with adverse side effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-Aβ antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-Aβ treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model with an intervention paradigm early during amyloidogenesis. Long-term treatment with anti-Aβ results in a robust and dose-dependent lowering of amyloid plaque pathology, with a higher efficiency for reducing diffuse over dense-core plaque deposition. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and α-Synuclein, as well as immune-cell-related proteins. Bulk RNA-seq revealed a dose-dependent attenuation of disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) protein, a major i...