MiR-195 dependent roles of mitofusin2 in the mitochondrial dysfunction of hippocampal neurons in SAMP8 mice.
Abnormal gene expression, including mRNAs, and microRNAs (miRNA), have been identified in the development of Alzheimer's disease (AD). Although mitofusin2 (mfn2) has been found to be down-regulated in the neurons from hippocampus and cortex in AD patients, little is known about its roles and the regulatory mechanisms in the pathogenesis of AD. This study was performed to investigate the roles of mfn2 protein and its upstream regulatory mechanism in the progression of AD using a senescence accelerated mouse prone-8 (SAMP8) model. The results of quantitative real-time PCR and western blot revealed that mfn2 expression displayed a consistent decrease with aging in the hippocampus of SAMP8 than did age-matched SAMR1 mice. The luciferase activity assay combined with mutational analysis confirmed the binding site of miR-195 to the 3' -untranslated region (3'-UTR) of mfn2 mRNA. Furthermore, miR-195 inhibitor or antigomir induced the higher level expression of mfn2 protein in vitro and in vivo. In addition, exogenous expression of miR-195 decreased the mitochondrial membrane potential (MMP) of the HT-22 cells by targeting mfn2. In conclusion, these results indicated that deregulation of mfn2 might be involved in mitochondrial dysfunction during the progression of AD, and its decreased expression was regulated at least in part by miR-195 in AD mice. The abnormal expression of miR-195 played a potential role in mitochondrial disorder by targeting mfn2 in hippocampus of SAMP8 mice. Therefore, upregulation of mfn2 protein by inhibiting miR-195 might be a potential new therapeutic strategy for treatment of AD.
Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang 050031, PR China; Burn Engineering Center of Hebei Province, Shijiazhuang 050031, PR China.
Rui
R
Zhang
Burn Engineering Center of Hebei Province, Shijiazhuang 050031, PR China; Department of Endocrinology, The First Hospital of Hebei Medical University, Shijiazhuang 050031, PR China.
Huimin
H
Zhou
Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang 050031, PR China.
Lei
L
Jiang
Department of Endocrinology, The First Hospital of Hebei Medical University, Shijiazhuang 050031, PR China.
Yueran
Y
Mao
Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang 050031, PR China.
Ximing
X
Cui
Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang 050031, PR China; Burn Engineering Center of Hebei Province, Shijiazhuang 050031, PR China.
Bing
B
Xie
Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang 050031, PR China.
Dongsheng
D
Cui
Department of Orthopedics, The First Hospital of Hebei Medical University, Shijiazhuang 050031, PR China.
Hui
H
Wang
Burn Engineering Center of Hebei Province, Shijiazhuang 050031, PR China.
Qingfu
Q
Zhang
Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang 050031, PR China; Burn Engineering Center of Hebei Province, Shijiazhuang 050031, PR China. Electronic address: sjxu66@hotmail.com.
Shunjiang
S
Xu
D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008815:Mice, Inbred Strains; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
C569389:MIRN195a microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse
Alzheimer's disease (AD); Hippocampus; MicroRNA; Mitofusin 2 (mfn2); SAM mice; miR-195