Zhou Xinhua, Zhu Zeyu, Kuang Shaoming, Huang Kaipeng, Li Yueping, Wang Yuqiang, Chen Haiyun, Hoi Maggie Pui Man, Xu Benhong, Yang Xifei, Zhang Zaijun
Guangzhou Medical Research Institute of Infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510440, China.
State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-Cerebrovascular Diseases, Institute of New Drug Research, Jinan University, Guangzhou 511436, China.
Pharmaceuticals (Basel). 2024 Jul 30;17(8):1005. doi: 10.3390/ph17081005.
Alzheimer's disease (AD) is a neurodegenerative disorder associated with age. A wealth of evidence indicates that the amyloid β (Aβ) aggregates result from dyshomeostasis between Aβ production and clearance, which plays a pivotal role in the pathogenesis of AD. Consequently, therapies targeting Aβ reduction represent a promising strategy for AD intervention. Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative with potential for the treatment of AD. Previously, we demonstrated that TBN markedly enhanced cognitive functions and decreased the levels of Aβ, APP, BACE 1, and hyperphosphorylated tau in 3×Tg-AD mice. However, the mechanism by which TBN inhibits Aβ deposition is still unclear. In this study, we employed APP/PS1 mice treated with TBN (60 mg/kg, ig, bid) for six months, and N2a/APP695swe cells treated with TBN (300 μM) to explore the mechanism of TBN in Aβ reduction. Our results indicate that TBN significantly alleviated cognitive impairment and reduced Aβ deposition in APP/PS1 mice. Further investigation of the underlying mechanisms revealed that TBN decreased the expression of APP and BACE1, activated the AMPK/mTOR/ULK1 autophagy pathway, inhibited the PI3K/AKT/mTOR/ULK1 autophagy pathway, and decreased the phosphorylation levels of JNK and ERK in APP/PS1 mice. Moreover, TBN was found to significantly reduce the mRNA levels of APP and BACE1, as well as those of SP1, CTCF, TGF-β, and NF-κB, transcription factors involved in regulating gene expression. Additionally, TBN was observed to decrease the level of and increase the levels of and in the N2a/APP695swe cells. These findings indicate that TBN may reduce Aβ levels likely by reducing APP expression by regulating APP gene transcriptional factors and miRNAs, reducing BACE1 expression, and promoting autophagy activities.
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病。大量证据表明，淀粉样β（Aβ）聚集体是由Aβ产生与清除之间的动态失衡导致的，这在AD的发病机制中起关键作用。因此，针对降低Aβ的疗法是AD干预的一种有前景的策略。川芎嗪硝基氧化物（TBN）是一种新型川芎嗪衍生物，具有治疗AD的潜力。此前，我们证明TBN可显著增强3×Tg-AD小鼠的认知功能，并降低Aβ、APP、BACE 1和过度磷酸化tau的水平。然而，TBN抑制Aβ沉积的机制仍不清楚。在本研究中，我们使用经TBN（60 mg/kg，灌胃，每日两次）处理6个月的APP/PS1小鼠，以及经TBN（300 μM）处理的N2a/APP695swe细胞，以探究TBN降低Aβ的机制。我们的结果表明，TBN可显著减轻APP/PS1小鼠的认知障碍并减少Aβ沉积。对潜在机制的进一步研究表明，TBN降低了APP和BACE1的表达，激活了AMPK/mTOR/ULK1自噬途径，抑制了PI3K/AKT/mTOR/ULK1自噬途径，并降低了APP/PS1小鼠中JNK和ERK的磷酸化水平。此外，发现TBN可显著降低APP和BACE1的mRNA水平，以及参与调节基因表达的转录因子SP1、CTCF、TGF-β和NF-κB的mRNA水平。此外，观察到TBN可降低N2a/APP695swe细胞中的 水平，并增加 和 的水平。这些发现表明，TBN可能通过调节APP基因转录因子和微小RNA来降低APP表达、降低BACE1表达并促进自噬活性，从而降低Aβ水平。
