Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
Neurobiol Aging. 2011 Nov;32(11):1949-63. doi: 10.1016/j.neurobiolaging.2009.12.010. Epub 2010 Jan 6.
Insulin-degrading enzyme (IDE), an enzyme that primarily degrades insulin, has recently been demonstrated to play a significant role in the catabolism of amyloid β (Aβ) protein in the brain. Reduced IDE expression and/or activity have been associated with the etiology and development of Alzheimer's disease (AD). Using three model systems, the present investigation provides the first documentation indicating that estrogen robustly regulates the expression of IDE in normal, menopausal and early-stage AD brains. In vitro analyses in primary cultures of rat hippocampal neurons revealed that 17β-estradiol (17β-E2) increased IDE in both mRNA and protein levels in a time-dependent manner. Further pharmacological analyses indicated that 17β-E2-induced IDE expression was dependent upon estrogen receptor (ER) β and required activation of phosphatidylinositol 3-kinase (PI3-K). In vivo analyses in adult female rats revealed a brain region-specific responsive profile. Ovariectomy (OVX) induced a significant decline in IDE expression in the hippocampus, which was prevented by 17β-E2. Neither OVX nor 17β-E2 affected IDE expression in the cerebellum. In vivo analyses in triple transgenic AD (3xTg-AD) female mice revealed an inverse correlation between the age-related increase in Aβ load and the decrease in IDE expression in the hippocampal formation. Treatment with 17β-E2 attenuated Aβ accumulation/plaque formation and elevated hippocampal IDE expression in 12-month-old 3xTg-AD OVX mice. Collectively, these findings indicate that 17β-E2 regulates IDE expression in a brain region-specific manner and such a regulatory role in the hippocampus, mediated by an ERβ/PI3-K pathway, could serve as a direct mechanism underlying estrogen-mediated preventative effect against AD when initiated at the onset of menopause.
胰岛素降解酶（IDE）是一种主要降解胰岛素的酶，最近研究表明它在大脑中淀粉样β（Aβ）蛋白的分解代谢中起着重要作用。IDE 表达和/或活性降低与阿尔茨海默病（AD）的病因和发展有关。本研究使用了三个模型系统，首次提供了证据表明，雌激素可强烈调节正常、绝经和早期 AD 大脑中 IDE 的表达。在原代培养的大鼠海马神经元的体外分析中，发现 17β-雌二醇（17β-E2）以时间依赖性方式增加了 IDE 的 mRNA 和蛋白水平。进一步的药理学分析表明，17β-E2 诱导的 IDE 表达依赖于雌激素受体（ER）β，并且需要激活磷脂酰肌醇 3-激酶（PI3-K）。在成年雌性大鼠的体内分析中，揭示了一种脑区特异性反应模式。卵巢切除术（OVX）导致海马中 IDE 表达显著下降，而 17β-E2 可预防这种下降。OVX 或 17β-E2 均不影响小脑的 IDE 表达。在三重转基因 AD（3xTg-AD）雌性小鼠的体内分析中，发现 Aβ负荷随年龄增长的增加与海马区 IDE 表达的下降呈负相关。17β-E2 治疗可减轻 12 月龄 3xTg-AD OVX 小鼠的 Aβ 蓄积/斑块形成，并提高海马区 IDE 表达。总之，这些发现表明，17β-E2 以脑区特异性方式调节 IDE 表达，这种在海马区的调节作用，通过 ERβ/PI3-K 途径介导，可能成为绝经后早期开始的雌激素对 AD 预防作用的直接机制。
