Cathepsin D deficiency induces oxidative damage in brain pericytes and impairs the blood-brain barrier
Cathepsin D deficiency induces oxidative damage in brain pericytes and impairs the blood-brain barrier
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DOI：
10.1016/j.mcn.2014.12.002
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发表时间：
2015-01-01
影响因子：
3.5
通讯作者：
Nakanishi, Hiroshi
中科院分区：
文献类型：
--
作者：
Okada, Ryo;Wu, Zhou;Nakanishi, Hiroshi
最近的证据表明，外周血单核细胞（PBMC）有助于神经元蜡样脂褐质沉着症（NCL）和溶酶体贮积病患者神经病理学变化的发病机制。为了检查由于组织蛋白酶 D (CatD) 缺乏导致血脑屏障 (BBB) 通透性可能增加以及由此导致的 PBMC 浸润（这是先天性 NCL 发病的潜在过程），我们检查了 CatD(-/-) 小鼠脑血管的结构变化。因此，出生后第24天（P24）Cat1D（-/-）小鼠大脑皮层脑血管的平均直径明显大于野生型小鼠。此外，Cat1D(-/-)小鼠脑周细胞的平均数量在P16时开始显着下降，并在P24时几乎消失，并且在P12时脑周细胞中首次检测到氧化DNA损伤。电子显微镜检查显示，大脑周细胞充满致密的颗粒体、细胞质空泡和脂滴。在 CatD(-)/(-) 小鼠的大脑皮层中也发现了以充满致密颗粒体的分段核为特征的 PBMC 浸润。当将表达增强型绿色荧光蛋白（GFP）的转基因大鼠制备的原代培养小胶质细胞注射到颈总动脉时，在CatD（-/-）小鼠的脑实质中检测到了GFP阳性小胶质细胞，但在野生型小鼠中未检测到。此外，胃酶抑素 A（一种特定的天冬氨酸蛋白酶抑制剂）可诱导分离的脑周细胞中线粒体衍生的活性氧 (ROS) 产生，从而降低细胞活力。这些观察结果表明，由于 CatD 缺乏导致溶酶体储存增加，导致脑周细胞氧化损伤，随后导致血管直径增加、BBB 通透性增强和 PBMC 浸润。因此，保护大脑周细胞免受溶酶体储存诱导的氧化应激可能是先天性 NCL 的替代治疗策略。 (C) 2014 Elsevier Inc. 保留所有权利。
Recent evidence suggests that peripheral blood mononuclear cells (PBMCs) contribute to the pathogenesis of neuropathological changes in patients with neuronal ceroid lipofuscinosis (NCL) and lysosomal storage diseases. In order to examine the possible increase in the permeability of the blood brain-barrier (BBB) and resultant infiltration of PBMCs due to cathepsin D (CatD) deficiency, a process underlying the onset of congenital NCL, we examined structural changes in brain vessels in CatD(-/-) mice. Consequently, the mean diameter of the brain vessels in the cerebral cortex on postnatal day 24 (P24) was significantly larger in Cat1D(-/-) mice than in wild-type mice. Furthermore, the mean number of brain pericytes in Cat1D(-/-) mice began to decline significantly on P16 and almost disappeared on P24, and oxidative DNA damage was first detected in brain pericytes on P12. Examinations with electron microscopy revealed that brain pericytes were laden with dense granular bodies, cytoplasmic vacuoles and lipid droplets. The infiltration of PBMCs characterized by segmented nucleus laden with dense granular bodies was also noted in the cerebral cortex of CatD(-)/(-) mice. When primary cultured microglia prepared from enhanced green fluorescent protein (GFP)-expressing transgenic rats were injected into the common carotid artery, GFP-positive microglia were detected in the brain parenchyma of CatD(-/-), but not wild-type, mice. Moreover, pepstatin A, a specific aspartic protease inhibitor, induced mitochondria-derived reactive oxygen species (ROS) production in the isolated brain pericytes, which decreased the cell viability. These observations suggest that increased lysosomal storage due to CatD deficiency causes oxidative damage in brain pericytes, subsequently resulting in an increased vessel diameter, enhanced permeability of the BBB and the infiltration of PBMCs. Therefore, protecting brain pericytes against lysosomal storage-induced oxidative stress may represent an alternative treatment strategy for congenital NCL. (C) 2014 Elsevier Inc. All rights reserved.