Cerebrolysin™ efficacy in a transgenic model of tauopathy: role in regulation of mitochondrial structure.
Cerebrolysin™ efficacy in a transgenic model of tauopathy: role in regulation of mitochondrial structure.
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DOI：
10.1186/1471-2202-15-90
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发表时间：
2014-07-21
期刊：
影响因子：
2.4
通讯作者：
Masliah E
中科院分区：
文献类型：
--
作者：
Rockenstein E;Ubhi K;Trejo M;Mante M;Patrick C;Adame A;Novak P;Jech M;Doppler E;Moessler H;Masliah E
阿尔茨海默氏病（AD）和额颞叶痴呆（FTLD）是老年人群中痴呆的常见原因，对于老年人群，可用的治疗选择有限。这些病症与Tau积累相关。我们之前已经证明，CerebrolysinTM（CBL），一种具有神经营养作用的神经肽混合物，通过减少过度磷酸化的Tau，改善AD的淀粉样前体蛋白（APP）转基因（tg）小鼠模型的行为缺陷和神经病理学改变。CBL已在AD的临床试验中进行了测试，但其在FTLD中的潜在有益作用尚不清楚。为此目的，我们试图研究CBL在tau蛋白病的tg模型中的作用。因此，用CBL处理在mThy-1启动子和GSK 3 β（以增强Tau磷酸化）下表达突变型Tau的双tg小鼠，并进行神经病理学评价。与单Tau tg小鼠相比，Tau/GSK 3 β双tg模型显示海马中Tau磷酸化和神经变性水平升高。CBL处理降低了Tau/GSK 3 β双tg小鼠齿状回中Tau磷酸化水平以及颞叶皮层和海马中锥体神经元的变性。有趣的是，Tau/GSK 3 β双tg小鼠也显示出动力蛋白相关蛋白-1（Drp-1）水平升高，这是一种水解GTP的蛋白质，是线粒体分裂所必需的。Tau/GSK 3 β双tg小鼠中线粒体的超微结构分析表明，与非tg小鼠相比，线粒体的数量和碎片增加。CBL治疗使Drp-1水平正常化并恢复线粒体结构。这些结果表明，CBL改善tau蛋白病模型中神经退行性病理的能力可能涉及减少过度磷酸化的Tau的积累和减少与Tau相关的线粒体生物发生的改变。
Alzheimer’s Disease (AD) and Fronto temporal lobar dementia (FTLD) are common causes of dementia in the aging population for which limited therapeutical options are available. These disorders are associated with Tau accumulation. We have previously shown that CerebrolysinTM (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the behavioral deficits and neuropathological alterations in amyloid precursor protein (APP) transgenic (tg) mouse model of AD by reducing hyper-phosphorylated Tau. CBL has been tested in clinical trials for AD, however it’s potential beneficial effects in FTLD are unknown. For this purpose we sought to investigate the effects of CBL in a tg model of tauopathy. Accordingly, double tg mice expressing mutant Tau under the mThy-1 promoter and GSK3β (to enhance Tau phosphorylation) were treated with CBL and evaluated neuropathologically. Compared to single Tau tg mice the Tau/GSK3β double tg model displayed elevated levels of Tau phosphorylation and neurodegeneration in the hippocampus. CBL treatment reduced the levels of Tau phosphorylation in the dentate gyrus and the degeneration of pyramidal neurons in the temporal cortex and hippocampus of the Tau/GSK3β double tg mice. Interestingly, the Tau/GSK3β double tg mice also displayed elevated levels of Dynamin-related protein-1 (Drp-1), a protein that hydrolyzes GTP and is required for mitochondrial division. Ultrastructural analysis of the mitochondria in the Tau/GSK3β double tg mice demonstrated increased numbers and fragmentation of mitochondria in comparison to non-tg mice. CBL treatment normalized levels of Drp-1 and restored mitochondrial structure. These results suggest that the ability of CBL to ameliorate neurodegenerative pathology in the tauopathy model may involve reducing accumulation of hyper-phosphorylated Tau and reducing alterations in mitochondrial biogenesis associated with Tau.
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影响因子：
4
作者：
Masliah, Eliezer
通讯作者：
Masliah, Eliezer
影响因子：
3.5
作者：
Fuster-Matanzo, Almudena;Llorens-Martin, Maria;Hernandez, Felix
通讯作者：
Hernandez, Felix
影响因子：
6
作者：
Cairns, Nigel J.;Neumann, Manuela;Mackenzie, Ian R. A.
通讯作者：
Mackenzie, Ian R. A.
影响因子：
3.5
作者：
Manczak, Maria;Reddy, P. Hemachandra
通讯作者：
Reddy, P. Hemachandra
影响因子：
16.2
作者：
DuBoff B;Götz J;Feany MB
通讯作者：
Feany MB