Amyloid‐β immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer’s Disease mice

Background Amyloid‐related imaging abnormalities (ARIA) have been identified as the most common and serious adverse events caused by pathological changes in the cerebral vasculature during several recent anti‐amyloid‐b (Aß) immunotherapy trials. However, the cellular and molecular mechanisms underlying how amyloid immunotherapy enhances cerebral amyloid angiopathy (CAA)‐mediated alterations of vascular permeability and microhemorrhages are not currently understood. Interestingly, brain perivascular macrophages have been implicated in regulating CAA deposition and cerebrovascular function however, additional studies are required to understand how perivascular macrophages play a role in enhancing CAA‐related vascular permeability and microhemorrhages associated with amyloid immunotherapy. Methods We study immune responses induced by amyloid targeting antibodies and CAA‐mediated microhemorrhages using histology and gene expression analyses in AD mouse models and primary culture settings. Results In the present study, we show 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 findings demonstrate that Aß antibodies engaged at CAA deposits are associated with the activation of perivascular macrophages and the upregulation of vascular permeability related genes. Whether this leads to increased susceptibility to microhemorrhages remains to be seen. Additional studies need to be performed to establish the role of CD169+ perivascular macrophages in enhancing CAA‐mediated vascular permeability, plasma protein extravasation, and infiltration of monocytes associated with microhemorrhages.