Neuroscience Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
Mol Neurodegener. 2023 Aug 30;18(1):59. doi: 10.1186/s13024-023-00649-w.
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.
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.
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.
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.
在最近几项抗淀粉样蛋白-β（Aβ）免疫疗法试验中，淀粉样相关成像异常（ARIA）已被确定为导致脑血管病理学变化的最常见和最严重的不良事件。然而，目前尚不清楚淀粉样蛋白免疫疗法如何增强脑淀粉样血管病（CAA）介导的血管通透性改变和微出血的细胞和分子机制。有趣的是，脑周细胞已被牵连到调节 CAA 沉积和脑血管功能，然而，需要进一步的研究来了解周细胞如何在增强与淀粉样蛋白免疫疗法相关的 CAA 相关血管通透性和微出血中发挥作用。
在这项研究中，我们使用组织学和基因表达分析检查了靶向淀粉样蛋白的抗体和 CAA 诱导的微出血在阿尔茨海默病（AD）小鼠模型和原代培养系统中引起的免疫反应。
在本研究中，我们证明抗 Aβ（3D6）免疫疗法导致血管淀粉样沉积物形成抗体免疫复合物，并诱导 CD169 周细胞激活。我们表明，通过抗体介导的 Fc 受体信号激活的巨噬细胞在体外表现出炎症信号和细胞外基质重塑基因（如 Timp1 和 MMP9）的表达增加，并在体内证实了这些关键发现。最后，我们证明了血浆蛋白的血管通透性增强和血管淀粉样沉积物周围炎症单核细胞的募集，这与脑微出血中的含铁血黄素沉积有关，提示激活的周细胞在 Aβ 免疫疗法中的多维作用。
总之，我们的研究建立了 CAA 沉积物中结合的 Aβ 抗体、周细胞的激活以及参与血管通透性的基因上调之间的联系。然而，这种现象对微出血易感性的影响仍有待充分阐明。需要进一步的研究来确定 CD169+周细胞在增强 CAA 介导的血管通透性、血浆蛋白外渗以及与微出血相关的免疫细胞浸润中的精确作用。
