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.

T-006 是一种衍生自四甲基吡嗪 (TMP) 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 预防性治疗对阿尔茨海默病 (AD) 模型的影响并确定 T-006 的靶点，我们将 T-006 (3 mg/kg) 灌胃给阿尔茨海默病 (AD) 转基因小鼠。 APP/PS1-2xTg 和 APP/PS1/Tau-3xTg）分别为 6 个月和 8 个月。T-006 在两种 AD 小鼠模型和靶向线粒体相关蛋白 α-F1-ATP 合酶 (ATP5A) 中长期给药后改善了认知能力。T-006 显着降低了 3xTg 小鼠中磷酸化 tau、总 tau 和 APP 的表达，同时增加了突触相关蛋白的表达。此外，T-006 调节 JNK 和 mTOR-ULK1 通路以降低 p-tau 和总 tau 水平。