This study investigates the potential therapeutic effects of sodium valproate (VPA) and WT161, a novel HDAC6 selective inhibitor, on Alzheimer's disease (AD) by regulating the expression of APP secretases. The research utilized both cellular and mouse models of AD, including N2a-APPswe cells and APP/PS1 transgenic mice. Key findings include: 1. **Expression Regulation**: VPA and WT161 downregulated the expression of multiple HDACs, such as HDAC1 and HDAC6, in both cell and mouse models. They also affected the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). 2. **Mechanistic Insights**: RNA interference and vitamin C induction confirmed that the expression of APP and APP secretases is regulated by HDAC1 and HDAC6, with the JNK pathway acting as an intermediate link. This regulatory process effectively reduced Aβ deposition and improved cognitive function in AD mice. 3. **Cognitive Impairment Amelioration**: Both VPA and WT161 significantly improved the cognitive function of AD mice, as assessed by the nest-building test, novel object recognition test, and Morris water maze test. 4. **Brain Tissue Analysis**: WT161 was detected in the brains of AD mice, confirming its ability to cross the blood-brain barrier. Treatment with VPA and WT161 reduced Aβ deposition in the cerebral cortex, hippocampus, and entorhinal cortex. 5. **Conclusion**: The study highlights the HDAC6-JNK-APP secretases cascade as a critical pathway through which VPA and WT161 exert their therapeutic effects on AD. The safety and efficacy of these drugs were also evaluated, providing preclinical evidence for their potential use in AD treatment. Keywords: VPA, WT161, Alzheimer's disease, Histone deacetylase, Aβ deposition, Cognitive functionThis study investigates the potential therapeutic effects of sodium valproate (VPA) and WT161, a novel HDAC6 selective inhibitor, on Alzheimer's disease (AD) by regulating the expression of APP secretases. The research utilized both cellular and mouse models of AD, including N2a-APPswe cells and APP/PS1 transgenic mice. Key findings include: 1. **Expression Regulation**: VPA and WT161 downregulated the expression of multiple HDACs, such as HDAC1 and HDAC6, in both cell and mouse models. They also affected the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). 2. **Mechanistic Insights**: RNA interference and vitamin C induction confirmed that the expression of APP and APP secretases is regulated by HDAC1 and HDAC6, with the JNK pathway acting as an intermediate link. This regulatory process effectively reduced Aβ deposition and improved cognitive function in AD mice. 3. **Cognitive Impairment Amelioration**: Both VPA and WT161 significantly improved the cognitive function of AD mice, as assessed by the nest-building test, novel object recognition test, and Morris water maze test. 4. **Brain Tissue Analysis**: WT161 was detected in the brains of AD mice, confirming its ability to cross the blood-brain barrier. Treatment with VPA and WT161 reduced Aβ deposition in the cerebral cortex, hippocampus, and entorhinal cortex. 5. **Conclusion**: The study highlights the HDAC6-JNK-APP secretases cascade as a critical pathway through which VPA and WT161 exert their therapeutic effects on AD. The safety and efficacy of these drugs were also evaluated, providing preclinical evidence for their potential use in AD treatment. Keywords: VPA, WT161, Alzheimer's disease, Histone deacetylase, Aβ deposition, Cognitive function