CSF transthyretin neuroprotection in a mouse model of brain ischemia
CSF transthyretin neuroprotection in a mouse model of brain ischemia
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DOI：
10.1111/j.1471-4159.2010.07047.x
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发表时间：
2010-12-01
影响因子：
4.7
通讯作者：
Saraiva, Maria Joao
中科院分区：
文献类型：
--
作者：
Santos, Sofia Duque;Lambertsen, Kate Lykke;Saraiva, Maria Joao
脑缺血引起的脑损伤是世界范围内人类死亡和身体/认知残疾的主要原因。在实验上，脑缺血可以通过永久性大脑中动脉闭塞手术诱导。利用该模型，我们研究了甲状腺素运载蛋白在缺血性中风中的影响。甲状腺素运载蛋白（TTR）通常负责在血液和CSF中运输甲状腺激素和视黄醇。我们发现，TTR空小鼠（TTR-/-）没有表现出显着差异，在大脑中动脉永久闭塞后24小时与TTR+/+对照同窝小鼠相比，皮层梗死。然而，与TTR+/+ HSF 1 +/-小鼠相比，TTR-/-HSF 1 +/-小鼠的皮质梗死、脑水肿和小胶质细胞-白细胞反应显著增加。出乎意料的是，我们观察到新的TTR分布在整个梗死，定位于分解的β-微管蛋白III+神经元和细胞碎片。通过RNAi特异性消除肝脏中的TTR合成对梗死中的TTR分布没有影响，表明观察到的TTR浸润来自CSF而不是来自血清。“原位”杂交和真实的时间PCR结果证实了这一发现，排除了梗死和梗死周围区域存在甲状腺素运载蛋白mRNA。我们的数据表明，在热休克反应受损的条件下，CSF TTR有助于控制神经元细胞死亡、水肿和炎症，从而影响脑缺血中濒危神经元的存活。
P>Brain injury caused by ischemia is a major cause of human mortality and physical/cognitive disability worldwide. Experimentally, brain ischemia can be induced surgically by permanent middle cerebral artery occlusion. Using this model, we studied the influence of transthyretin in ischemic stroke. Transthyretin (TTR) is normally responsible for the transport of thyroid hormones and retinol in the blood and CSF. We found that TTR null mice (TTR-/-) did not show significant differences in cortical infarction 24 h after permanent middle cerebral artery occlusion compared with TTR+/+ control littermates. However, TTR null mice, heterozygous for the heat-shock transcription factor 1 (TTR-/-HSF1+/- mice), which compromised the stress response, showed a significant increase in cortical infarction, cerebral edema and the microglial-leukocyte response compared with TTR+/+HSF1+/- mice. Unexpectedly, we observed novel TTR distribution throughout the infarct, localized to disintegrated beta-tubulin III+ neurons and cell debris. Specific elimination of TTR synthesis in the liver by RNAi had no effect on TTR distribution in the infarct, indicating that the observed TTR infiltration derived from CSF and not from the serum. This finding is corroborated by results from 'in situ' hybridization and real time PCR that excluded the presence of transthyretin mRNA in the infarct and peri-infarct areas. Our data suggest that in conditions of a compromised heat-shock response, CSF TTR contributes to control neuronal cell death, edema and inflammation, thereby influencing the survival of endangered neurons in cerebral ischemia.