β-分泌酶抑制剂对tau过磷酸化大鼠β-CTF代谢的影响及机制研究  

The Effects and Mechanisms of β-secretase Inhibitor on the Processing of β-CTF in Tau Hyperphosphorylated Rat Model

作　　者：陈红媛[1] 王永闯 李立[1] 王莉[2] 俞春江[1] 

机构地区：[1]哈尔滨医科大学附属第二临床医院神经内科,黑龙江哈尔滨150000 [2]哈尔滨医科大学附属第二临床医院老年病科,黑龙江哈尔滨150000

出　　处：《现代生物医学进展》2017年第2期237-241,共5页Progress in Modern Biomedicine

基　　金：黑龙江省卫生计生委科研基金项目(2014-337);黑龙江省博士后基金项目(LBH-Z15135)

摘　　要：目的:在tau过磷酸化大鼠中,通过检测淀粉样前体蛋白(amyloid precursor protein,APP)C末端片段的表达,研究抑制β-分泌酶(BACE1)对其代谢的影响及机制。方法:24只SD大鼠随机分为四组,包括正常对照组、假手术组、OA组、OA+BACE1抑制剂组。Western blot法检测β-CTF、APP及BACE1表达;RT-PCR法检测APP及BACE1;水迷宫检测大鼠行为学。结果:OA组β-CTF表达显著增加(p<0.05),而OA+BACE1抑制剂组与OA组相比,β-CTF表达减少(p<0.05);四组大鼠的APP在蛋白及mRNA水平表达无显著差别(p>0.05);OA组BACE1在蛋白及mRNA水平的表达增加,而OA+BACE1抑制剂组BACE1的蛋白表达较OA组减少(p<0.05),两组大鼠mRNA表达水平无明显差异(p>0.05)。OA+BACE1抑制剂组大鼠在给予BACE1抑制剂后行为学有所改善(p<0.05)。结论:(1)tau过磷酸化通过促进神经元内BACE1表达,导致APP代谢途径发生转变,从而引起β-CTF表达增加;(2)β-CTF表达增加可引起tau过磷酸化大鼠行为学改变;(3)抑制BACE1可改善大鼠的学习及记忆能力,支持BACE1作为AD的治疗靶点。Objective： To study the effects and mechanisms of β-secretase inhibitor on the processing of β-CTF in tau hyperphosphorylated rat model. Methods： Twenty-four male SD rats were randomly divided into four groups, including the control group,the sham group, the OA group and the OA＋BACE1 group. For each group of rats, Western blot was used to analyze the level of amyloid precursor protein C-terminal fragment（APP-CTF）, APP and BACE1. Meanwhile, RT-PCR was performed to detect the mRNA levels of APP and BACE1. With water maze test, abilities of learning and memory were detected. Results： It was found that β-CTF significantly increased in the OA group（p〈0.05）, while decreased in the OA ＋ BACE1 inhibitor group compared to the OA group（p〈0.05）. There was no statistically significant difference in the protein and mRNA levels of APP among the four groups（p〉0.05）. The protein and mRNA levels of BACE1 significantly increased in the OA group（p〈0.05）. The protein levels of BACE1 in the OA＋BACE1 inhibitor group decreased compared to the control group（p 0.05）, and there was no difference in the mRNA levels between the two groups（p 〉0.05）.With water maze test, the behavior of rats in the OA＋BACE1 inhibitor group were restored（p〈0.05）. Conclusion： ⑴Hyperphosphorylated tau protein induced the increase of BACE1 expression, thus the pathway of APP processing had been shifted, and the level of β-CTF increased in neurons, ⑵The increase of β-CTF impaired the behavior of rats, ⑶ Inhibition of BACE1 could improve the abilities of study and memory in rats, indicating that BACE1 might be a therapeutic target of AD.

关 键 词：阿尔茨海默病 淀粉样前体蛋白C末端片段 BACE1 tau过磷酸化 

分 类 号：R741.02[医药卫生—神经病学与精神病学] R749.16[医药卫生—临床医学]