Blood-CNS Barrier Impairment in ALS patients versus an animal model.
Blood-CNS Barrier Impairment in ALS patients versus an animal model.
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DOI：
10.3389/fncel.2014.00021
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发表时间：
2014
影响因子：
5.3
通讯作者：
Sanberg PR
中科院分区：
文献类型：
--
作者：
Garbuzova-Davis S;Sanberg PR
肌萎缩侧索硬化症(ALS)是一种严重的神经退行性疾病，其发病机制复杂且知之甚少。近年来，血-中枢神经系统屏障(B-CNS-B)的改变被认为是可能加重运动神经元损伤的关键因素。关于ALS微血管病理的大多数发现已经在突变的超氧化物歧化酶(SOD1)啮齿动物模型中确定，确定了疾病发展过程中的屏障损伤，这可能类似地发生在携带SOD1突变的家族性ALS患者中。然而，我们对B-CNS-B在散发性肌萎缩侧索硬化症(SALS)中的能力的了解有限。我们最近发现SALS患者死后延髓和脊髓组织的灰质和白质微血管的结构和功能受损，提示弥漫性屏障损伤。虽然在ALS和SALS患者的SOD1突变动物模型中都显示出许多屏障损害的迹象(内皮细胞变性、毛细血管渗漏、血管周围水肿、紧密连接蛋白下调和微出血)，但其他致病性屏障改变迄今仅在SALS患者中被发现。SALS患者的周细胞变性、血管周围IV型胶原扩张和白质毛细血管异常是ALS SOD1动物模型中尚未注意到的重大屏障相关病理。在目前的综述中，这些在ALS患者和动物模型之间血液-中枢神经系统屏障损伤的重要差异被讨论，这可能意味着屏障转运机制的改变。了解ALS患者和动物模型之间屏障状况的差异可能对开发有效的治疗方法至关重要。
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with a complicated and poorly understood pathogenesis. Recently, alterations in the blood–Central Nervous System barrier (B-CNS-B) have been recognized as a key factor possibly aggravating motor neuron damage. The majority of findings on ALS microvascular pathology have been determined in mutant superoxide dismutase (SOD1) rodent models, identifying barrier damage during disease development which might similarly occur in familial ALS patients carrying the SOD1 mutation. However, our knowledge of B-CNS-B competence in sporadic ALS (SALS) has been limited. We recently showed structural and functional impairment in postmortem gray and white matter microvessels of medulla and spinal cord tissue from SALS patients, suggesting pervasive barrier damage. Although numerous signs of barrier impairment (endothelial cell degeneration, capillary leakage, perivascular edema, downregulation of tight junction proteins, and microhemorrhages) are indicated in both mutant SOD1 animal models of ALS and SALS patients, other pathogenic barrier alterations have as yet only been identified in SALS patients. Pericyte degeneration, perivascular collagen IV expansion, and white matter capillary abnormalities in SALS patients are significant barrier related pathologies yet to be noted in ALS SOD1 animal models. In the current review, these important differences in blood–CNS barrier damage between ALS patients and animal models, which may signify altered barrier transport mechanisms, are discussed. Understanding discrepancies in barrier condition between ALS patients and animal models may be crucial for developing effective therapies.
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