Anti-Aβ immunotherapy-mediated amyloid clearance attenuates microglial activation without inducing exhaustion at residual plaques

de Weerd, L.; Hummel, S.; Mueller, S. A.; Paris, I.; Sandmann, T.; Eichholtz, M.; Gröger, R.; Englert, A.; Wagner, S.; Ha, C.; Davis, S. S.; Warkins, V.; Xia, D.; Nuscher, B.; Berghofer, A.; Reich, M.; Feiten, A. F.; Schlepckow, K.; Willem, M.; Lichtenthaler, S. F.; Lewcock, J. W.; Monroe, K. M.; Brendel, M.; Haass, C.

doi:10.1101/2025.04.10.645950

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bioRxiv · 10.1101/2025.04.10.645950

Anti-Aβ immunotherapy-mediated amyloid clearance attenuates microglial activation without inducing exhaustion at residual plaques

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Abstract

Anti-amyloid {beta}-peptide (A{beta}) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimers disease. Efficient amyloid plaque clearance has been proven in clinical trials testing anti-A{beta} antibodies, with the impact on cognitive endpoints correlating with the extent of plaque 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-A{beta} antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-A{beta} treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model. Mice were treated weekly with anti-A{beta} antibody from 4-8 months of age. Long-term treatment with anti-A{beta} results in a robust and dose-dependent removal of amyloid plaque pathology, with a higher efficiency for removing diffuse over dense-core plaques. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and -Synuclein, as well as immune cell related proteins. Bulk RNA-seq revealed a dose-dependent decrease in brain-wide disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering receptor of myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around remaining plaques remains high regardless of treatment dose. In addition, microglia surrounding remaining plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen presenting and immune signalling proteins. These findings demonstrate that long-term chronic anti-A{beta} mediated removal of A{beta} leads to a dose dependent decrease in brain-wide microglial DAM activation and neurodegeneration, while microglia at residual plaques display a combined DAM and antigen presenting phenotype that suggests a continued treatment response. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/645950v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@6d1a49org.highwire.dtl.DTLVardef@d8c14dorg.highwire.dtl.DTLVardef@7ae330org.highwire.dtl.DTLVardef@1d96cc3_HPS_FORMAT_FIGEXP M_FIG Graphical abstract: Schematic overview of the effects of chronic long-term anti-A treatment in APP-SAA mice Schematic was created with BioRender.com C_FIG

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de Weerd, L., Hummel, S., Mueller, S. A., Paris, I., Sandmann, T., Eichholtz, M., Gröger, R., Englert, A., Wagner, S., Ha, C., Davis, S. S., Warkins, V., Xia, D., Nuscher, B., Berghofer, A., Reich, M., Feiten, A. F., Schlepckow, K., Willem, M., Lichtenthaler, S. F., Lewcock, J. W., Monroe, K. M., Brendel, M., Haass, C.. 2025-04-17. Anti-Aβ immunotherapy-mediated amyloid clearance attenuates microglial activation without inducing exhaustion at residual plaques. https://doi.org/10.1101/2025.04.10.645950

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