miR-34a, a microRNA up-regulated in a double transgenic mouse model of Alzheimer's disease, inhibits bcl2 translation.
MicroRNAs (miRNAs) are short noncoding regulatory RNA molecules that modulate protein expression by inhibiting mRNA translation or promoting mRNA degradation. However, little is understood about the roles of miRNAs in Alzheimer's disease. During a research for miRNAs that are differentially expressed in cerebral cortex of APPswe/PSDeltaE9 mice (a model for Alzheimer's disease) and age-matched controls, one candidate miRNA that is relatively highly expressed, miR-34a, was studied further because sequence analysis suggested a likely interaction with the 3'-untranslated region of bcl2 mRNA. We show that the expression of miR-34a is inversely correlated with the protein level of bcl2 in APPswe/PSDeltaE9 mice and age-matched controls, and miR-34a expression directly inhibits bcl2 translation in SH-SY5Y cells. No effect on bcl2 mRNA level was observed. Western blot analysis of active caspase-3 showed higher levels in APPswe/PSDeltaE9 mice and stable transfecant cell line of miR-34a than in controls. Consistently, miR-34a knockdown through antisense LNA oligonucleotides increased the level of bcl2 protein in SH-SY5Y cells, which was accompanied by a decrease of active caspase-3. These findings suggested that bcl2 is an important functional target for miR-34a, and the abnormal expression of miR-34a may contribute to the pathogenesis of Alzheimer's disease, at least in part by affecting the expression of bcl2.
Wang
Xiaoying
X
Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanli, Chaoyang District, Beijing, China. wang_xy1896@yahoo.com.cn
Liu
Peng
P
Zhu
Hua
H
Xu
Yanfeng
Y
Ma
Chunmei
C
Dai
Xiaowei
X
Huang
Lan
L
Liu
Yali
Y
Zhang
Lianfeng
L
Qin
Chuan
C
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D053764:Presenilin-1 / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016229:Amyloid beta-Peptides; D035683:MicroRNAs; D053764:Presenilin-1; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse; D053148:Caspase 3