摘要
Background： Prematurely menopausal women have a doubled lifetime risk of dementia and a 5-fold increased risk of mortality from neuro- logical disorders, but the molecular mechanisms underlying these risks remain unclear. We hypothesized that ischemia-induced amyloidogenesis may be enhanced in the hippocampus following prolonged loss of ovarian 17β-estradiol （E2）, which could contribute to these phenomena. Methods： The current study used a rat model of premature surgical menopause （10-week bilateral ovariectomy） with E2 therapy either initiated immediately （short-term E2 deprivation （STED）） or delayed to the end of the ovariectomy period （long-term E2 deprivation （LTED））. One week after continuous, subcutaneous E2 therapy, we subjected animals to 10-min global cerebral ischemia （GCI） to assess the effect of LTED on ischemia-induced amyloidogenesis in the hippocampal CA1. Results： The present study revealed that while hippocampal β-amyloid （Aβ） is not typically enhanced following GCI, there is a rapid, robust elevation of endogenous Aβ in LTED females after GCI. In STED females, we observed that GCI attenuates and E2 maintains A Disintegrin and Metalloprotease 10 （ADAM 10） expression in the hippocampal CA1, and concurrently, GCI increases and E2 decreases BACE1 levels in the same region. Intriguingly, however, we observed a loss of E2 regulation of ADAM 10, ADAM 17, and BACE 1 levels in the hippocampal CA I of LTED females, which provides mechanistic evidence for the enhanced post-ischemic Aβ load following LTED. We also observed loss of E2 regulation of tau hyperphosphorylation in LTED females subjected to GCI. Conclusion： Collectively, these studies partially explain the enhanced risk of dementia and mortality from neurological disorders seen in prematurely menopausal women and support timely initiation of E2 therapy to yield maximum neurological benefit.
背景:研究发现,过早绝经的女性患痴呆的风险加倍,死干神经功能障碍的风险也增加5倍,但其分子机制还不明确。本研究试图探讨卵巢1 7β-雌二醇(E2)持续降低是否可能促进海马区局部缺血引起的淀粉状蛋白生成。方法:用已建造的早期手术性更年期大鼠模型(双侧卵巢切除术10周),在手术后立即给予E2(短期E2缺乏,STED)或卵巢切除术后期给予E2(长期E2缺乏,LTED)。在连续1周皮下注射E2后,对于动物进行全脑缺血10 min,再评价LTED对缺血诱导的海马CA1区淀粉样蛋白生成的作用。结果:海马区β淀粉样蛋白(Aβ)水平在全脑缺血后没有明显增加,而LTED雌鼠在全脑缺血后内源性Aβ水平快速稳健提高。在STED的雌鼠,我们观察到全脑缺血后减少ADAM10在海马CA1区的表达,而E2治疗能保持ADAM10在海马CA1区的表达水平。同时,全脑缺血后引起BACEl的增强,而E2可以在相同脑区域降低BACE1水平。然而,我们在LTED雌鼠观察到E2治疗失去了在海马CA1区对ADAM 10、ADAM 17和BACE1水平的调节,说明早期内源性雌激素长期缺乏会加重脑缺血后导致的Aβ-生成。同时,我们还观察到,LTED雌鼠全脑缺血后,E2还失去了对tau蛋白高度磷酸化的调节,为体内雌激素水平下降和脑缺血所导致的粉状蛋白增加的机制提供了证据。结论:本研究部分解释了过早绝经的妇女有高风险患痴呆和过早死亡的机制,并认为及时补充E2会使得神经系统得到最大的保护作用。
基金
supported by a Pre-doctoral Fellowship from the American Heart Association to ELS.(12PRE11530009)
a Research Grant from the National Institute of Neurological Disorders and Stroke
National Institutes of Health,USA to DWB(NS050730)
