Reduced early hypoxic/ischemic brain damage is associated with increased GLT-1 levels in mice expressing mutant (P301L) human tau.
Reduced early hypoxic/ischemic brain damage is associated with increased GLT-1 levels in mice expressing mutant (P301L) human tau.
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DOI：
10.1016/j.brainres.2008.10.022
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发表时间：
2009-01-09
期刊：
影响因子：
2.9
通讯作者：
Bi X
中科院分区：
文献类型：
--
作者：
Liao G;Zhou M;Cheung S;Galeano J;Nguyen N;Baudry M;Bi X
tau蛋白的突变与一组被称为tau蛋白病的神经退行性疾病有关。为了研究过表达含P301L突变的人tau蛋白是否也会影响中风诱导的脑损伤，我们在年轻成年的P301L tau转基因小鼠中进行了缺氧/缺血（H/I）处理。令人惊讶的是，在H/I诱导24小时后，转基因小鼠的脑梗死体积明显小于野生型小鼠。TUNEL染色也显示在H/I后转基因小鼠的脑凋亡较少。H/I导致野生型小鼠（而非转基因小鼠）皮质中半胱天冬酶激活产生的tau片段显著增加，以及残基T231处的tau磷酸化显著降低。与野生型小鼠相比，转基因小鼠在H/I后钙蛋白酶和半胱天冬酶 - 3的激活也减少了，这体现在钙蛋白酶或半胱天冬酶 - 3产生的特定血影蛋白降解产物水平较低。最后，转基因小鼠大脑中胶质谷氨酸转运体GLT - 1的基础水平高于野生型小鼠。这些结果支持这样一种观点，即转基因小鼠中GLT - 1水平的提高通过减少细胞外谷氨酸积累以及随后的钙蛋白酶和半胱天冬酶激活，从而减轻了H/I诱导的脑损伤。
Mutations in tau proteins are associated with a group of neurodegenerative diseases, termed tauopathies. To investigate whether over-expressing human tau with P301L mutation also affects stroke-induced brain damage, we performed hypoxia/ischemia (H/I) in young adult P301L tau transgenic mice. Surprisingly, brain infarct volume was significantly smaller in transgenic mice compared to wild-type mice 24 h after H/I induction. TUNEL staining also revealed less brain apoptosis in transgenic mice following H/I. H/I resulted in a significant increase in tau fragments generated by caspase activation and a marked decrease in tau phosphorylation at residue T231 in cortex of wild-type but not transgenic mice. Activation of calpain and caspase-3 following H/I was also reduced in transgenic compared to wild-type mice, as reflected by lower levels of the specific spectrin breakdown products generated by calpain or caspase-3. Finally, basal levels of the glial glutamate transporter, GLT-1, were higher in brains of transgenic as compared to wild-type mice. These results support the idea that enhanced levels of GLT-1 in transgenic mice are responsible for reducing H/I-induced brain damage by decreasing extracellular glutamate accumulation and subsequent calpain and caspase activation.
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影响因子：
6
作者：
Lin, WL;Lewis, J;Dickson, DW
通讯作者：
Dickson, DW
影响因子：
5.7
作者：
Didenko, VV;Ngo, H;Baskin, DS
通讯作者：
Baskin, DS
DOI：
10.1016/s1050-3862(96)00167-2
发表时间：
1996-12-01
期刊：
GENETIC ANALYSIS-BIOMOLECULAR ENGINEERING
影响因子：
--
作者：
Borchelt, DR;Davis, J;Price, DL
通讯作者：
Price, DL
影响因子：
30.8
作者：
Lewis, J;McGowan, E;Hutton, M
通讯作者：
Hutton, M
DOI：
10.1073/pnas.151253098
发表时间：
2001-07-17
影响因子：
11.1
作者：
Bi, XN;Yong, AP;Lynch, G
通讯作者：
Lynch, G