在阿尔茨海默病小鼠模型中,淀粉样蛋白-β(Aβ)免疫疗法诱发的微出血与血管炎症和脑血管损伤有关。

IF 14.9 1区 医学 Q1 NEUROSCIENCES
Xavier Taylor, Harun N Noristani, Griffin J Fitzgerald, Herold Oluoch, Nick Babb, Tyler McGathey, Lindsay Carter, Justin T Hole, Pascale N Lacor, Ronald B DeMattos, Yaming Wang
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引用次数: 0

摘要

背景:抗淀粉样蛋白-β(Aβ)免疫疗法试验显示,淀粉样蛋白相关成像异常(ARIA)是与脑血管病理改变有关的最普遍、最严重的不良反应。最近的研究强调,血管周围巨噬细胞和外周免疫细胞的浸润在调节脑血管损伤方面起着至关重要的作用。具体来说,脑淀粉样血管病(CAA)沉积物上的 Aβ 抗体会引发血管周围巨噬细胞的活化和血管通透性相关基因的上调。然而,要了解巨噬细胞活化的直接下游后果,即可能加剧与Aβ免疫疗法有关的CAA相关血管通透性和微出血,还需要进一步的研究:本研究在阿尔茨海默病(AD)小鼠微出血模型中使用RNA原位杂交、组织学和数字空间图谱分析方法研究了淀粉样蛋白靶向抗体诱导的免疫反应和CAA诱导的微出血:在本研究中,我们证明了巴比妥珠单抗小鼠代用品(3D6)会诱发严重的血管损伤,导致平滑肌细胞丢失和血脑屏障(BBB)破坏。此外,数字空间图谱(DSP)显示,不同的免疫反应导致了血管损伤,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损失和血管纤维化有关。最后,RNA 原位杂交确定了两个不同的 Trem2+ 巨噬细胞亚群,分别代表血管淀粉样蛋白沉积物周围的组织驻留巨噬细胞和单核细胞衍生巨噬细胞。总之,这些发现凸显了免疫激活和血管损伤在驱动微出血发生中的多方面作用:总之,我们的研究在 CAA-Aβ 抗体免疫复合物的形成、免疫激活和导致平滑肌细胞损失的血管损伤之间建立了重要联系。然而,这一级联反应对微小出血发生的全面影响还需要进一步探讨。还需要进行更多的研究,以揭示导致微出血的精确分子机制、不同免疫群的相互作用以及各种 Trem2+ 巨噬细胞群在 Aβ 免疫疗法中发挥的功能作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Amyloid-β (Aβ) immunotherapy induced microhemorrhages are linked to vascular inflammation and cerebrovascular damage in a mouse model of Alzheimer's disease.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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来源期刊
Molecular Neurodegeneration
Molecular Neurodegeneration 医学-神经科学
CiteScore
23.00
自引率
4.60%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Molecular Neurodegeneration, an open-access, peer-reviewed journal, comprehensively covers neurodegeneration research at the molecular and cellular levels. Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and prion diseases, fall under its purview. These disorders, often linked to advanced aging and characterized by varying degrees of dementia, pose a significant public health concern with the growing aging population. Recent strides in understanding the molecular and cellular mechanisms of these neurodegenerative disorders offer valuable insights into their pathogenesis.
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