Che Hui, Sun Li-Hua, Guo Fei, Niu Hui-Fang, Su Xiao-Lin, Bao Ya-Nan, Fu Zidong Donna, Liu Huai-Lei, Hou Xu, Yang Bao-Feng, Ai Jing
Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province, China.
Cell Physiol Biochem. 2014;33(1):11-22. doi: 10.1159/000356646. Epub 2014 Jan 2.
Aging is associated with the gradual cognitive decline and shows the typical senile plaque formation in the brain, which results from the aggregation of beta amyloid (Aβ) peptide following the abnormal proteolytic processing of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. Accumulating evidence indicates that several microRNAs (miRNAs) are involved in the Alzheimer's disease (AD) by regulating the expression of APP and BACE1 proteins. However, the cognitive ability and the expression profile of the APP- and BACE1-associated miRNAs in the middle-aged population are largely unknown.
The learning and memory ability in rats were determined by Morris Water Maze test. The protein levels of APP and BACE1 were detected by western blotting. The quantitative polymerase chain reaction was used to identify the miRNAs levels in forebrain cortex and the hippocampus.
Middle-aged rats have declined learning ability without changes in the memory ability, and increased APP and BACE1 protein expression in the forebrain cortex. Computational analysis using Targetscan and Pictar databases reveals that totally 4 predicted miRNAs have conserved binding site with APP, namely miR-106b, -17-5p, -153, -101. All of them showed decreased expression in both the forebrain cortex and hippocampus. Among the 10 predicted miRNAs targeting BACE1, different expression profiles were identified in the forebrain cortex (decreased: miR-9, -19a, -135a, -15b, -16, -195, -29c, -214; increased: miR-124; no change: miR-141) and the hippocampus (decreased: miR-9, -15b, -16, -195, -29c, -124; increased: miR-19a, -135a, -214, -141) in the middle-aged rats compared with the young rats.
Our results provided the first evidence that middle-aged rats have begun displaying cognitive disability with abnormal expression of APP- and BACE1-related miRNAs in the hippocampus and forebrain cortex.
衰老与认知功能逐渐衰退相关，并在大脑中出现典型的老年斑形成，这是由于淀粉样前体蛋白（APP）经β-分泌酶（BACE1）和γ-分泌酶异常蛋白水解加工后，β淀粉样蛋白（Aβ）肽聚集所致。越来越多的证据表明，几种微小RNA（miRNA）通过调节APP和BACE1蛋白的表达参与阿尔茨海默病（AD）。然而，中年人群中与APP和BACE1相关的miRNA的认知能力和表达谱在很大程度上尚不清楚。
通过莫里斯水迷宫试验测定大鼠的学习和记忆能力。采用蛋白质印迹法检测APP和BACE1的蛋白水平。运用定量聚合酶链反应鉴定前脑皮质和海马中的miRNA水平。
中年大鼠学习能力下降，但记忆能力无变化，且前脑皮质中APP和BACE1蛋白表达增加。使用Targetscan和Pictar数据库进行的计算分析显示，共有4种预测的miRNA与APP具有保守结合位点，即miR-106b、-17-5p、-153、-101。它们在前脑皮质和海马中的表达均降低。在10种预测的靶向BACE1的miRNA中，中年大鼠前脑皮质（降低：miR-9、-19a、-135a、-15b、-16、-195、-29c、-214；升高：miR-124；无变化：miR-141）和海马（降低：miR-9、-15b、-16、-195、-29c、-124；升高：miR-19a、-135a、-214、-141）与年轻大鼠相比呈现不同的表达谱。
我们的结果首次证明，中年大鼠已开始表现出认知障碍，海马和前脑皮质中与APP和BACE1相关的miRNA表达异常。
