Dataset Information

Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations.

ABSTRACT: Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. We found that reductions in amyloid and neuritic dystrophy during acute treatment were accompanied by microglial and astrocytic activation, and microglial recruitment to plaques and adoption of an aducanumab-specific pro-phagocytic and pro-degradation transcriptomic signature, indicating a role for microglia in aducanumab-mediated Aβ clearance. Reductions in Aβ and dystrophy were sustained 15 but not 30 wk after discontinuation, and reaccumulation of plaques coincided with loss of the microglial aducanumab signature and failure of microglia to reactivate. This suggests that despite the initial benefit from treatment, microglia are unable to respond later to restrain plaque reaccumulation, making further studies on the effect of amyloid-directed immunotherapy withdrawal crucial for assessing long-term safety and efficacy.

SUBMITTER: Cadiz MP

PROVIDER: S-EPMC10791560 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations.

Cadiz Mika P MP Gibson Katelin A KA Todd Kennedi T KT Nascari David G DG Massa Nashali N Lilley Meredith T MT Olney Kimberly C KC Al-Amin Md Mamun MM Jiang Hong H Holtzman David M DM Fryer John D JD

The Journal of experimental medicine 20240116 2

Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. We found that reductions in amyloid and neuritic dystrophy during acute treatment were accompanied by microglial and astrocytic activation, an ...[more]

PMID: 38226975

Similar Datasets

Project description: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.

Project description:BackgroundThree years of treatment with either sublingual or subcutaneous allergen immunotherapy has been shown to be effective and to induce long-term tolerance. The Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy (GRASS) trial demonstrated that 2 years of treatment through either route was effective in suppressing the response to nasal allergen challenge, although it was insufficient for inhibition 1 year after discontinuation.ObjectiveWe sought to examine in the GRASS trial the time course of immunologic changes during 2 years of sublingual and subcutaneous immunotherapy and for 1 year after treatment discontinuation.MethodsWe performed multimodal immunomonitoring to assess allergen-specific CD4 T-cell properties in parallel with analysis of local mucosal cytokine responses induced by nasal allergen exposure and humoral immune responses that included IgE-dependent basophil activation and measurement of serum inhibitory activity for allergen-IgE binding to B cells (IgE-facilitated allergen binding).ResultsAll 3 of these distinct arms of the immune response displayed significant and coordinate alterations during 2 years of allergen desensitization, followed by reversal at 3 years, reflecting a lack of a durable immunologic effect. Although frequencies of antigen-specific TH2 cells in peripheral blood determined by using HLA class II tetramer analysis most closely paralleled clinical outcomes, IgE antibody-dependent functional assays remained inhibited in part 1 year after discontinuation.ConclusionTwo years of allergen immunotherapy were effective but insufficient for long-term tolerance. Allergen-specific TH2 cells most closely paralleled the transient clinical outcome, and it is likely that recurrence of the T-cell drivers of allergic immunity abrogated the potential for durable tolerance. On the other hand, the persistence of IgE blocking antibody 1 year after discontinuation might be an early indicator of a protolerogenic mechanism.

Dataset Information

Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations.

Publications

Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets