Scott Erin L, Zhang Quan-Guang, Han Dong, Desai Bhavna N, Brann Darrell W
Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA 30912, USA.
Steroids. 2013 Jun;78(6):624-32. doi: 10.1016/j.steroids.2012.11.004. Epub 2012 Nov 22.
Surgically menopausal women incur a 2- to 5-fold increased risk for dementia and mortality from neurological diseases, but the mechanisms underlying these increased risks remain unclear. Previously, we demonstrated that after global cerebral ischemia (GCI), 17β-estradiol (E2 or estrogen) suppresses hippocampal elevation of the Wnt antagonist Dickkopf-1 (Dkk1), a neurodegenerative factor. We, thus, hypothesized that prolonged loss of E2 may lead to dysregulation of neural Dkk1 and Wnt/β-Catenin signaling, which could contribute to an increased risk of neurodegeneration. To test this hypothesis, we examined the effect of short-term (1 week - STED) and long-term E2 deprivation (10 weeks - LTED) via ovariectomy upon basal and E2-regulated Dkk1 levels and Wnt/β-Catenin signaling in the hippocampal CA1 region following GCI. In STED rats, E2 exerted robust neuroprotection against GCI, suppressed post-ischemic elevation of Dkk1, and enhanced pro-survival Wnt/β-Catenin signaling, effects that were lost in LTED rats. Intriguingly, LTED rats displayed modest basal changes in Dkk1 and survivin expression. Further work showed that c-Jun N-terminal Kinase (JNK) mediated GCI-induced changes in Dkk1 and survivin, and JNK inhibition afforded neuroprotection in LTED rats. Finally, we extended our findings to natural aging, as 24-month-old, reproductively senescent female rats also displayed a modest increase in basal Dkk1 in the CA1, which consistently co-localized with the apoptotic marker TUNEL after GCI and coincided with a loss of E2 neuroprotection. As a whole, this study supports the "critical period hypothesis" and further suggests that perimenopausal estradiol replacement may prevent neurodegenerative changes in the hippocampus by maintaining favorable Wnt/β-Catenin signaling.
手术绝经的女性患痴呆症和神经疾病导致死亡的风险增加2至5倍，但这些风险增加背后的机制仍不清楚。此前，我们证明，在全脑缺血（GCI）后，17β-雌二醇（E2或雌激素）可抑制神经退行性因子Wnt拮抗剂Dickkopf-1（Dkk1）在海马体中的升高。因此，我们推测，E2的长期缺失可能导致神经Dkk1和Wnt/β-连环蛋白信号失调，这可能导致神经退行性变风险增加。为了验证这一假设，我们通过卵巢切除术研究了短期（1周 - STED）和长期E2剥夺（10周 - LTED）对GCI后海马CA1区基础和E2调节的Dkk1水平以及Wnt/β-连环蛋白信号的影响。在STED大鼠中，E2对GCI具有强大的神经保护作用，抑制缺血后Dkk1的升高，并增强促生存的Wnt/β-连环蛋白信号，而这些作用在LTED大鼠中消失。有趣的是，LTED大鼠在Dkk1和生存素表达方面表现出适度的基础变化。进一步的研究表明，c-Jun氨基末端激酶（JNK）介导了GCI诱导的Dkk1和生存素变化，并且JNK抑制在LTED大鼠中提供了神经保护作用。最后，我们将研究结果扩展到自然衰老，因为24个月大、生殖衰老的雌性大鼠在CA1区的基础Dkk1也有适度增加，在GCI后与凋亡标志物TUNEL始终共定位，并且与E2神经保护作用的丧失一致。总体而言，本研究支持“关键期假说”，并进一步表明围绝经期雌二醇替代可能通过维持有利的Wnt/β-连环蛋白信号来预防海马体中的神经退行性变化。
