Department of Neurology, Fujian Institute of Geriatrics, the Affiliated Union Hospital of Fujian Medical University, People's Republic of China.
Eur J Pharmacol. 2012 Jan 30;675(1-3):15-21. doi: 10.1016/j.ejphar.2011.11.039. Epub 2011 Dec 7.
The level of β-site APP-cleaving enzyme 1 (BACE1) has been documented to increase in the brains of patients with Alzheimer's disease, which has resulted in elevation of β-amyloid (Aβ) peptides. As a transcription factor binding site of the BACE1 promoter, peroxisome proliferator-activated receptor-γ (PPARγ) response element regulates the activity of the BACE1 promoter activity, indicating that PPARγ may become a potential target for Alzheimer's disease treatment. Recent studies have demonstrated that ginsenoside Rg1 which is an effective component of extracts of ginseng can prevent memory loss and improve cognitive function in a variety of animal models. However, the underlying mechanism remains unclear. In the present study, we found that Rg1 decreased the levels of Aβ₁₋₄₀ and Aβ₁₋₄₂ secreted in N2a-APP695 cells. The expression levels of both BACE1 mRNA and protein as well as β-CTFs, a cleavaged C-terminal fragment of APP by BACE1, were reduced in cells treated with Rg1. Moreover, Rg1 treatment led to a translocation of PPARγ from cytoplasm to nuclear. Intriguingly, Rg1, like pioglitazone (a PPARγ agonist), suppressed BACE1 activity in N2a-APP695 cells, while its effect on BACE1 activity was attenuated by GW9662 (a PPARγ antagonist). These results indicate that Rg1 may be a PPARγ agonist to enhance the binding of nuclear PPARγ to the BACE1 promoter, which may in turn inhibit the transcription and translation of BACE1, suppress the activity of BACE1, and ultimately attenuate Aβ generation. Therefore, ginsenoside Rg1 may serve as a promising agent in modulating Aβ-related pathology in Alzheimer's disease.
β-位点 APP 裂解酶 1（BACE1）的水平已被证明在阿尔茨海默病患者的大脑中增加，这导致β-淀粉样蛋白（Aβ）肽的升高。作为 BACE1 启动子的转录因子结合位点，过氧化物酶体增殖物激活受体-γ（PPARγ）反应元件调节 BACE1 启动子活性，表明 PPARγ 可能成为阿尔茨海默病治疗的潜在靶点。最近的研究表明，人参提取物中的有效成分人参皂苷 Rg1 可以预防各种动物模型的记忆丧失和改善认知功能。然而，其潜在机制尚不清楚。在本研究中，我们发现 Rg1 降低了 N2a-APP695 细胞中分泌的 Aβ₁₋₄₀和 Aβ₁₋₄₂的水平。用 Rg1 处理的细胞中 BACE1 mRNA 和蛋白的表达水平以及 β-CTFs（BACE1 切割 APP 的 C 端片段）均降低。此外，Rg1 处理导致 PPARγ 从细胞质转位到核内。有趣的是，Rg1 像吡格列酮（PPARγ 激动剂）一样，抑制了 N2a-APP695 细胞中的 BACE1 活性，而其对 BACE1 活性的影响被 GW9662（PPARγ 拮抗剂）减弱。这些结果表明，Rg1 可能是一种 PPARγ 激动剂，可增强核 PPARγ 与 BACE1 启动子的结合，从而抑制 BACE1 的转录和翻译，抑制 BACE1 的活性，并最终减弱 Aβ 的产生。因此，人参皂苷 Rg1 可能是一种有前途的调节剂，可调节阿尔茨海默病中与 Aβ 相关的病理学。
