The Tetramethylpyrazine Analogue T-006 Alleviates Cognitive Deficits by Inhibition of Tau Expression and Phosphorylation in Transgenic Mice Modeling Alzheimer's Disease
The Tetramethylpyrazine Analogue T-006 Alleviates Cognitive Deficits by Inhibition of Tau Expression and Phosphorylation in Transgenic Mice Modeling Alzheimer's Disease
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四甲基吡嗪类似物 T-006 通过抑制阿尔茨海默病转基因小鼠模型中的 Tau 表达和磷酸化来缓解认知缺陷
DOI：
10.1007/s12031-020-01762-x
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发表时间：
2021-01-05
影响因子：
3.1
通讯作者：
Wang, Yuqiang
中科院分区：
文献类型：
--
作者：
Zhang, Guiliang;Wu, Jiahui;Wang, Yuqiang
T-006是一种由川芎嗪(TMP)衍生而来的小分子化合物，具有治疗神经系统疾病的潜力。为了研究T-006对阿尔茨海默病(AD)模型的预防作用，并确定T-006的靶点，我们对阿尔茨海默病(AD)转基因小鼠(APP/PS1-2xTg和APP/PS1/Tau-3xTg)分别灌胃给予T-006(3 mg/kg)6个月和8个月。长期给药后，T-006改善了两种AD小鼠模型的认知能力，并靶向线粒体相关蛋白α-F1-ATP合成酶(ATP5A)。T-006显著降低3xTg小鼠突触相关蛋白的表达，显著降低磷酸化tau蛋白、总tau蛋白和APP的表达。此外，T-006还调节JNK和mTOR-ULK1通路，降低p-tau和总tau水平。我们的数据表明，T-006主要通过降低3xTg小鼠的p-tau和总tau水平来缓解认知能力下降，支持进一步研究其作为治疗AD的候选药物的发展。
T-006, a small-molecule compound derived from tetramethylpyrazine (TMP), has potential for the treatment of neurological diseases. In order to investigate the effect of T-006 prophylactic treatment on an Alzheimer's disease (AD) model and identify the target of T-006, we intragastrically administered T-006 (3 mg/kg) to Alzheimer's disease (AD) transgenic mice (APP/PS1-2xTg and APP/PS1/Tau-3xTg) for 6 and 8 months, respectively. T-006 improved cognitive ability after long-term administration in two AD mouse models and targeted mitochondrial-related protein alpha-F1-ATP synthase (ATP5A). T-006 significantly reduced the expression of phosphorylated-tau, total tau, and APP while increasing the expression of synapse-associated proteins in 3xTg mice. In addition, T-006 modulated the JNK and mTOR-ULK1 pathways to reduce both p-tau and total tau levels. Our data suggested that T-006 mitigated cognitive decline primarily by reducing the p-tau and total tau levels in 3xTg mice, supporting further investigation into its development as a candidate drug for AD treatment.