Hashemi Ezzat, Srivastava Isha N, Aguirre Alejandro, Yoseph Ezra T, Kaushal Esha, Awani Avni, Ryu Jae K, Akassoglou Katerina, Talebian Shahrzad, Chu Pauline, Pisani Laura, Musolino Patricia, Steinman Lawrence, Doyle Kristian, Robinson William H, Sharpe Orr, Cayrol Romain, Orchard Paul J, Lund Troy, Vogel Hannes, Lenail Max, Han May H, Bonkowsky Joshua L, Van Haren Keith P
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA.
Gladstone Institute for Neurological Disease, San Francisco, CA.
Ann Neurol. 2025 Feb;97(2):296-312. doi: 10.1002/ana.27117. Epub 2024 Oct 28.
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.
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.
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.
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 2025;97:296-312.
X连锁肾上腺脑白质营养不良（ALD）由过氧化物酶体基因ABCD1突变引起。超过半数携带ABCD1突变的男性会发生炎症性脑脱髓鞘（cALD），但其潜在机制仍不清楚，治疗方法也有限。我们试图建立并表征一种cALD小鼠模型，以促进对疾病机制的研究和治疗方法的开发。
我们使用免疫测定和免疫组织化学方法，评估cALD患者脑脊液（CSF）和死后脑组织中的新型分子标志物（白细胞介素18 [IL-18]）和已确立的分子标志物。我们采用一种双打击方法在Abcd1基因敲除小鼠中诱导出cALD表型，该方法结合了铜螯合剂和实验性自身免疫性脑脊髓炎模型。然后，我们使用磁共振成像（MRI）和免疫组织化学方法评估小鼠中cALD分子标志物的可靠性。
人类和小鼠的cALD病变具有共同的组织学特征，包括髓鞘吞噬、髓鞘丢失、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生。与野生型对照相比，Abcd1基因敲除小鼠表现出更严重的脑脱髓鞘、血脑屏障破坏和血管周围免疫细胞浸润。这种增强的炎症反应与更高水平的纤维蛋白沉积、氧化应激、脱髓鞘和轴突损伤相关。在人类和小鼠脑组织中，IL-18免疫反应性与血管周围单核细胞/巨噬细胞共定位。在cALD患者中，CSF中IL-18水平与MRI病变严重程度相关。
我们的结果表明，小鼠中Abcd1功能丧失易导致更严重的血脑屏障破坏、由外周免疫细胞浸润驱动的脑部炎症、脱髓鞘和轴突损伤，重现了人类cALD的特征。这种新型小鼠模型可能有助于揭示cALD的机制，并加速cALD治疗方法的开发。《神经病学纪事》2025年；97:296 - 312。
