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Chronic Aducanumab-mediated clearance of amyloid plaques decreases microglial activation and induces a unique microglial phenotype associated with antigen presentation

ABSTRACT: Anti-amyloid β-peptide (Aβ) 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-Aβ 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 α-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 Aβ 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE288801 | GEO | 2025/08/20

REPOSITORIES: GEO

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Project description:Background: ABCA1 has recently been identified as a novel genetic risk factor for Alzheimer’s disease. The major known role of ABCA1 in the brain is to transfer lipids onto lipid poor APOE. Given that APOEε4 is the strongest genetic risk factor for developing late onset Alzheimer’s disease, this recent finding implicates the cholesterol homeostatic pathway in the onset/progression of Alzheimer’s disease. microRNAs (miRs) are small RNA species that negatively regulate expression of their target genes. ABCA1 is regulated by miR-33, and loss of this miR significantly increases protein levels of ABCA1 and increases the lipidation of APOE. However, it is unknown if loss of miR-33 and subsequent increase in ABCA1 protein levels ameliorates amyloid pathology. Methods: We generated miR-33+/+;APP/PS1 and miR-33-/-;APP/PS1 mice to determine changes in amyloid-beta (Aβ) peptides and amyloid plaque formation utilizing biochemical and histological analyses. In addition to amyloid pathology, we assessed if deletion of miR-33 altered the activation of glial cells in the brains of these mice. We utilized in vitro methods to determine if miR-33 alters the phagocytosis of Aβ aggregates. We utilized RNA-sequencing and mass spectrometry to identify the transcriptome and proteome regulation by miR-33 in the context of amyloid pathology. Results: Deletion of miR-33 dramatically reduces insoluble Aβ peptide levels and the deposition of amyloid plaques in APP/PS1 mice. In addition, we identified that astrocyte and microglial activation is markedly decreased in miR-33-/-;APP/PS1 mice through histological analyses. Intriguingly, we show that loss of miR-33 results in amyloid plaques that are more compact, potentially implicating enhanced microglial phagocytosis. We confirm in vitro that loss of miR-33 significantly increases microglial phagocytosis of Aβ aggregates. Our multi-omics analyses reveal that deletion of miR-33 regulates immune response in the context of amyloid pathology. Interestingly, we identified that WNT/Beta-catenin signaling is significantly upregulated in miR-33-/-;APP/PS1 mice. Conclusion: We confirm that the deletion of miR-33 increases APOE lipidation and significantly reduces amyloid pathology as well as glial activation in APP/PS1 mice. Our results agree with previous work identifying APOE lipidation as an important modulator of amyloid pathology. We show, for the first time, that loss of miR-33 increases the phagocytosis of Aβ by microglia. In total, we identify miR-33 as a promising target for the amelioration of amyloid pathology.

Project description:Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer’s disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1β in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2+ myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1β-induced plaque clearance. To date, however, the mechanisms of IL-1β-induced plaque clearance remain poorly understood. To determine whether IL-1β-induced plaque clearance is due to enhanced microglial phagocytosis of Aβ, APP/PS1 mice induced to express mature human IL-1β in the hippocampus via adenoviral transduction were treated with the Aβ fluorescent probe methoxy-X04 (MX04) and microglial internalization of Aβ was analyzed by flow cytometry and immunohistochemistry. We found that resident microglia (CD45loCD11b+) constituted >70% of the MX04+ cells in both control and IL-1β-treated conditions, and that <10% of MX04+ cells were recruited myeloid cells (CD45hiCD11b+). However, we found that IL-1β treatment did not augment the percentage of MX04+ microglia nor the quantity of Aβ internalized by individual microglia. Instead, we found that IL-1β treatment resulted in a significant increase in the total number of MX04+ microglia in the hippocampus due to IL-1β-induced proliferation. Consistent with these results, transcriptomic analyses revealed very similar gene expression profiles between MX04+ and MX04- microglia, indicating IL-1β does not drive enhanced expression of phagocytosis-related genes. By contrast, IL-1β treatment was associated with large-scale changes in the expression of genes related to proliferation, immune function and inflammation. Together, these studies demonstrate that IL-1β induces microglial proliferation and the expression of genes involved in inflammatory immune functions that may be related to Aβ clearance.

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Chronic Aducanumab-mediated clearance of amyloid plaques decreases microglial activation and induces a unique microglial phenotype associated with antigen presentation

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