Anti-amyloid-β (Aβ) immunotherapy trials have revealed amyloid-related imaging abnormalities (ARIA) as the most prevalent and serious adverse events linked to pathological changes in cerebral vasculature. Recent studies underscore the critical involvement of perivascular macrophages and the infiltration of peripheral immune cells in regulating cerebrovascular damage. Specifically, Aβ antibodies engaged at cerebral amyloid angiopathy (CAA) deposits trigger perivascular macrophage activation and the upregulation of genes associated with vascular permeability. Nevertheless, further research is needed to understand the immediate downstream consequences of macrophage activation, potentially exacerbating CAA-related vascular permeability and microhemorrhages linked to Aβ immunotherapy. This study investigates immune responses induced by amyloid-targeting antibodies and CAA-induced microhemorrhages using RNA in situ hybridization, histology and digital spatial profiling in an Alzheimer's disease (AD) mouse model of microhemorrhage. In the present study, we have demonstrated that bapineuzumab murine surrogate (3D6) induces profound vascular damage, leading to smooth muscle cell loss and blood–brain barrier (BBB) breakdown. In addition, digital spatial profiling (DSP) reveals that distinct immune responses contribute to vascular damage with peripheral immune responses and perivascular macrophage activation linked to smooth muscle cell loss and vascular fibrosis, respectively. Finally, RNA in situ hybridization identifies two distinct subsets of Trem2+ macrophages representing tissue-resident and monocyte-derived macrophages around vascular amyloid deposits. Overall, these findings highlight multifaceted roles of immune activation and vascular damage in driving the development of microhemorrhage. In summary, our study has established a significant link between CAA-Aβ antibody immune complex formation, immune activation and vascular damage leading to smooth muscle cell loss. However, the full implications of this cascade on the development of microhemorrhages requires further exploration. Additional investigations are warranted to unravel the precise molecular mechanisms leading to microhemorrhage, the interplay of diverse immune populations and the functional roles played by various Trem2+ macrophage populations in response to Aβ immunotherapy.

中文翻译：

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淀粉样蛋白 β （Aβ） 免疫疗法诱导的微出血与阿尔茨海默病小鼠模型中的血管炎症和脑血管损伤有关


抗淀粉样蛋白β （Aβ） 免疫治疗试验显示，淀粉样蛋白相关影像学异常 （ARIA） 是与脑血管病理变化相关的最普遍和最严重的不良事件。最近的研究强调了血管周围巨噬细胞和外周免疫细胞浸润在调节脑血管损伤中的关键作用。具体来说，参与脑淀粉样血管病 （CAA） 沉积的 Aβ 抗体触发血管周围巨噬细胞活化和与血管通透性相关的基因上调。然而，需要进一步的研究来了解巨噬细胞活化的直接下游后果，这可能会加剧与 Aβ 免疫治疗相关的 CAA 相关血管通透性和微出血。本研究在阿尔茨海默病 （AD） 微出血小鼠模型中使用 RNA 原位杂交、组织学和数字空间分析研究了淀粉样蛋白靶向抗体和 CAA 诱导的微出血诱导的免疫反应。在本研究中，我们已经证明 bapineuzumab 鼠替代物 （3D6） 诱导严重的血管损伤，导致平滑肌细胞丢失和血脑屏障 （BBB） 崩溃。此外，数字空间分析 （DSP） 显示，不同的免疫反应会导致血管损伤，外周免疫反应和血管周围巨噬细胞活化分别与平滑肌细胞丢失和血管纤维化有关。最后，RNA 原位杂交鉴定了 Trem2+ 巨噬细胞的两个不同亚群，代表血管淀粉样蛋白沉积物周围的组织驻留和单核细胞衍生的巨噬细胞。 总体而言，这些发现强调了免疫激活和血管损伤在驱动微出血发展中的多方面作用。综上所述，我们的研究建立了 CAA-Aβ 抗体免疫复合物形成、免疫激活和导致平滑肌细胞丢失的血管损伤之间的显着联系。然而，这种级联反应对微出血发展的全部影响需要进一步探索。需要进行更多研究，以揭示导致微出血的确切分子机制、不同免疫群体的相互作用以及各种 Trem2+ 巨噬细胞群体在响应 Aβ 免疫治疗中发挥的功能作用。