卵巢切除对APP/PS1双转基因小鼠脑内老年斑及自噬的影响

Effects of ovariectomy on autophagy and senile plaques in the brain of adult APP/PS1 double transgenic mice

目的研究雌激素对APP/PS1双转基因小鼠脑内老年斑及自噬的影响,探讨雌激素缺乏导致阿尔茨海默病(AD)的病理机制。方法将3月龄雌性APP/PS1双转基因AD模型小鼠分为卵巢切除组与假手术组,术后2个月采用免疫组化染色及透射电镜观察两组小鼠脑内老年斑及自噬功能的变化,同时检测自噬相关蛋白LC3、Beclin-1的表达情况。结果免疫组化结果显示,与假手术组相比,卵巢切除组小鼠脑内老年斑显著增加,分布更广,自噬相关蛋白LC3、Beclin-1阳性神经元数量均显著下降。电镜观察可见,与假手术组相比,卵巢切除组小鼠海马神经元及突起肿胀明显,暗神经元增加,神经元突起周围自噬小泡显著增多。结论雌激素缺乏可导致自噬泡成熟受阻、活性降低、自噬功能减弱,从而导致AD病理改变加重。

Objective To investigate the effect of ovarian estrogen on autophagy and senile plaques （SP） in the brain of adult APP/PS1 double transgenic mice, and inquire into the mechanism of Alzheimer disease （AD） neuropathogenesis due to estrogen deficiency. Methods APP/PS1 AD mice （3-month old） were divided into ovariectomy group （OVX-AD） and sham group （sham- AD）, Two months after operation, transmission electron microscopy （TEM） was employed to observe the morphological structures of the brains of AD model mice, and immunohistochemical staining was performed to examine the changes in SP and autophagy-related proteins LC3 and Beclin-1 in the brain of AD model mice. Results Immunohistochemical staining showed that the number of SP in the brain of OVX-AD mice incrcased significantly compared with that in sham-AD mice, and distribution of SP was observed more extensively, including the cortex and hippocampus. The autophagy related proteins LC3 and Beclin-1 positive neurons were decreased greatly in the OVX-AD mice brain compared with that of sham-AD mice. TEM revealed a larger number of swollen and dark neurons in hippocampus of OVX-AD mice, while more autophagosome was observed around the neuronal processes in OVX-AD mice brain compared with sham-AD mice. Conclusion Estrogen deficiency may lead to delayed maturation of autophagy, decrease the activity and weaken the function of autophagy, which in turn may result in aggravation of pathological features of AD.