Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Neurobiol Aging. 2012 Sep;33(9):2072-81. doi: 10.1016/j.neurobiolaging.2011.09.027. Epub 2011 Nov 4.
Tauopathies are characterized by progressive neurodegeneration caused by intracellular accumulation of hyperphosphorylated tau protein aggregates in the brain. The present study was designed to test whether a grape seed polyphenolic extract (GSPE) previously shown to inhibit tau protein aggregation in vitro could benefit tau-mediated neuropathology and behavior deficits in JNPL3 transgenic mice expressing a human tau protein containing the P301L mutation. Nine-month-old JNPL3 mice were treated with GSPE delivered through their drinking water for 6 months. We found that GSPE treatment significantly reduced the number of motor neurons immunoreactive for hyperphosphorylated and conformationally-modified tau in the ventral horns of the spinal cord identified using AT100, PHF-1, AT8, and Alz50 tau antibodies. This coincided with a drastically reduced level of hyperphosphorylated and sarcosyl-insoluble tau in spinal cord fractions. Furthermore, the reduction of tau pathology was accompanied by an improvement in the motor function assessed by a wire hang test. Collectively, our results suggest that GSPE can interfere with tau-mediated neurodegenerative mechanisms and ameliorate neurodegenerative phenotype in an animal model of tauopathy. Our studies support further evaluation of GSPE for preventing and/or treating of tauopathies in humans.
tau 病是以脑内过度磷酸化 tau 蛋白聚集导致进行性神经退行性变为特征的。本研究旨在测试先前已证明可抑制体外 tau 蛋白聚集的葡萄籽多酚提取物（GSPE）是否可有益于表达人 tau 蛋白 P301L 突变的 JNPL3 转基因小鼠的 tau 介导的神经病理学和行为缺陷。用含有 GSPE 的饮用水对 9 个月大的 JNPL3 小鼠进行 6 个月的处理。我们发现，GSPE 处理显著减少了使用 AT100、PHF-1、AT8 和 Alz50 tau 抗体鉴定的脊髓腹角中 AT100、PHF-1、AT8 和 Alz50 tau 抗体免疫反应性的磷酸化和构象修饰 tau 阳性的运动神经元的数量。这与脊髓分数中高度磷酸化和肌氨酸不可溶性 tau 的水平明显降低相一致。此外，tau 病理学的减少伴随着通过线悬挂试验评估的运动功能的改善。总的来说，我们的结果表明，GSPE 可以干扰 tau 介导的神经退行性机制，并改善 tau 病动物模型中的神经退行性表型。我们的研究支持进一步评估 GSPE 用于预防和/或治疗人类的 tau 病。
