Chronic Aducanumab-mediated clearance of amyloid plaques decreases microglial activation and induces a unique microglial phenotype associated with antigen presentation
Anti-amyloid ß-peptide (Aß) immune therapy was developed as treatment for Alzheimer's disease (AD) to reduce and prevent amyloid plaque pathology. This approach has proven successful in phase 3 clinical trials  of Aducanumab, Lecanemab and Donanemab. These antibodies induce robust amyloid plaque clearance, slow memory decline, and have beneficial effects on daily living activities.  The therapeutic effects correlate with the efficacy of plaque removal. Treatment is associated with adverse side-effects, such as oedema and haemorrhages (ARIA-E and -H), which are potentially linked to the induced immune response. To improve therapeutic safety, it is therefore imperative to understand the effects of anti-Aß antibody treatment on immune cell function. We investigated the effects of long-term chronic Aducanumab treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model. Mice were treated weekly with Aducanumab from 4-8 months of age. Long-term treatment with Aducanumab results in a robust and dose-dependent removal of amyloid plaque pathology. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including tau and a-synuclein. Consistent with a reduction of glucose uptake, the therapeutic effects were accompanied by reduced microglial activation. RNAseq confirmed a dose-dependent decrease in the disease-associated microglia (DAM) transcriptional signature of microglia, which is supported by a parallel decrease of Trem2 protein. However, genes associated with antigen-presentation were still increased after treatment. IHC confirms that Aducanumab treatment increases microglial clustering, as well as MHC-II expression around plaques and ELISA confirmed increased cytokine levels. These findings demonstrate that long-term chronic Aducanumab-mediated removal of Aß leads to a dose dependent decrease in microglial activation and neurodegeneration, but induces a unique antibody treatment-related microglial phenotype associated with antigen presentation, which may be related to plaques still present after the 4 months treatment period. Overall design: Homozygous APP-SAA knock-in mice were randomized into 5 treatment groups: (1) Untreated (4 months); (2) Isotype control, 10 mg/kg (8 months); (3) Aducanumab, 1 mg/kg (8 months); (4) Aducanumab, 3 mg/kg (8 months); (5) Aducanumab, 10 mg/kg (8 months). Each group (N=6) contained both male and female animals. Animals in the "Untreated" group were sacrificed at 4 months of age, when the 16-week treatments of the other groups began. Primary microglia were collected from the brain of each animal using magnetic activated cell sorting (MACS) with Cd11b microbeads.