X-遗传性肾上腺白质营养不良症脑部炎症性脱髓鞘的新型小鼠模型:对发病机制和潜在治疗靶点的洞察。

IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY
Ezzat Hashemi, Isha N Srivastava, Alejandro Aguirre, Ezra T Yoseph, Esha Kaushal, Avni Awani, Jae K Ryu, Katerina Akassoglou, Shahrzad Talebian, Pauline Chu, Laura Pisani, Patricia Musolino, Lawrence Steinman, Kristian Doyle, William H Robinson, Orr Sharpe, Romain Cayrol, Paul J Orchard, Troy Lund, Hannes Vogel, Max Lenail, May H Han, Joshua L Bonkowsky, Keith P Van Haren
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引用次数: 0

摘要

目的:X连锁肾上腺白质营养不良症(ALD)是由过氧化物酶体基因ABCD1突变引起的。半数以上的ABCD1基因突变雄性患者会患上炎性脑脱髓鞘症(cALD),但其潜在机制仍不清楚,治疗方法也很有限。我们试图建立一个 cALD 小鼠模型并描述其特征,以促进对疾病机制和疗法开发的研究:我们使用免疫测定和免疫组织化学方法评估了 cALD 患者脑脊液(CSF)和死后脑组织中的新分子标记物(白细胞介素 18 [IL-18])和已有分子标记物。我们采用一种结合了铜绿素和实验性自身免疫性脑脊髓炎模型的双击法,在 Abcd1 基因敲除小鼠中产生了 cALD 表型。然后,我们使用磁共振成像(MRI)和免疫组化技术评估了小鼠体内cALD分子标记的保真度:结果:人类和小鼠的cALD病变具有共同的组织学特征:髓鞘吞噬、髓鞘缺失、大量小胶质细胞活化、T细胞和B细胞浸润以及星形胶质细胞增多。与野生型对照组相比,Abcd1 基因敲除小鼠表现出更多的脑脱髓鞘、血脑屏障破坏和血管周围免疫细胞浸润。这种炎症反应的增强与更高水平的纤维蛋白沉积、氧化应激、脱髓鞘和轴突损伤有关。在人和小鼠脑组织中,IL-18免疫反应与血管周围单核细胞/巨噬细胞共定位。在cALD患者中,CSF IL-18水平与MRI病变严重程度相关:我们的研究结果表明,小鼠Abcd1功能缺失易导致更严重的血脑屏障破坏、外周免疫细胞浸润导致的脑部炎症、脱髓鞘和轴突损伤,这与人类cALD的特征如出一辙。这种新型小鼠模型可以揭示cALD的发病机制,并加速cALD疗法的开发。ann neurol 2024.
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets.

Objective: X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.

Methods: We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice.

Results: Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-knockout mice displayed more cerebral demyelination, blood-brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity.

Interpretation: Our results suggest loss of Abcd1 function in mice predisposes to more severe blood-brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2024.

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来源期刊
Annals of Neurology
Annals of Neurology 医学-临床神经学
CiteScore
18.00
自引率
1.80%
发文量
270
审稿时长
3-8 weeks
期刊介绍: Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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