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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2023

Open Access 01-12-2023 | Alzheimer's Disease | Research article

Amyloid-β (Aβ) immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer’s disease mice

Authors: Xavier Taylor, Isaiah M. Clark, Griffin J. Fitzgerald, Herold Oluoch, Justin T. Hole, Ronald B. DeMattos, Yaming Wang, Feng Pan

Published in: Molecular Neurodegeneration | Issue 1/2023

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Abstract

Background

Amyloid-related imaging abnormalities (ARIA) have been identified as the most common and serious adverse events resulting from pathological changes in the cerebral vasculature during several recent anti-amyloid-β (Aβ) immunotherapy trials. However, the precise cellular and molecular mechanisms underlying how amyloid immunotherapy enhances cerebral amyloid angiopathy (CAA)-mediated alterations in vascular permeability and microhemorrhages are not currently understood. Interestingly, brain perivascular macrophages have been implicated in regulating CAA deposition and cerebrovascular function however, further investigations are required to understand how perivascular macrophages play a role in enhancing CAA-related vascular permeability and microhemorrhages associated with amyloid immunotherapy.

Methods

In this study, we examined immune responses induced by amyloid-targeting antibodies and CAA-induced microhemorrhages using histology and gene expression analyses in Alzheimer’s disease (AD) mouse models and primary culture systems.

Results

In the present study, we demonstrate that anti-Aβ (3D6) immunotherapy leads to the formation of an antibody immune complex with vascular amyloid deposits and induces the activation of CD169+ perivascular macrophages. We show that macrophages activated by antibody mediated Fc receptor signaling have increased expression of inflammatory signaling and extracellular matrix remodeling genes such as Timp1 and MMP9 in vitro and confirm these key findings in vivo. Finally, we demonstrate enhanced vascular permeability of plasma proteins and recruitment of inflammatory monocytes around vascular amyloid deposits, which are associated with hemosiderin deposits from cerebral microhemorrhages, suggesting the multidimensional roles of activated perivascular macrophages in response to Aβ immunotherapy.

Conclusions

In summary, our study establishes a connection between Aβ antibodies engaged at CAA deposits, the activation of perivascular macrophages, and the upregulation of genes involved in vascular permeability. However, the implications of this phenomenon on the susceptibility to microhemorrhages remain to be fully elucidated. Further investigations are warranted to determine the precise role of CD169 + perivascular macrophages in enhancing CAA-mediated vascular permeability, extravasation of plasma proteins, and infiltration of immune cells associated with microhemorrhages.
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Metadata
Title
Amyloid-β (Aβ) immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer’s disease mice
Authors
Xavier Taylor
Isaiah M. Clark
Griffin J. Fitzgerald
Herold Oluoch
Justin T. Hole
Ronald B. DeMattos
Yaming Wang
Feng Pan
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2023
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-023-00649-w

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