title: Astrocytic CCAAT/Enhancer Binding Protein δ Regulates Neuronal Viability and Spatial Learning Ability via miR-135a.
abstract: The progression of Alzheimer's disease (AD) has been associated with astrocytes-induced neuroinflammation. However, the detailed mechanism of astrocytes associated with learning impairments and neuronal loss in AD is poorly defined. Here, we provide novel evidences that astrocytic miR-135a is critical for neuronal viability and spatial learning ability in vivo. The AppTg/Cebpd (-/-) mice showed a spatial learning improvement compared with the APPswe/PS1/E9 bigenic (AppTg) mice. miR-135a was found to be a CCAAT/enhancer binding protein δ (CEBPD) responsive miRNA and can repress the transcription of thrombospondin 1 (THBS1) / Thbs1 (mouse) via its 3'-untranslated region (3'UTR). We used different experimental approaches to attenuate the expression of CEBPD/Cebpd (mouse) or miR-135a in astrocytes and found the following results: increase in THBS1/Thbs1 expression, decrease in neuronal apoptosis, and increase in growth of neurites. Importantly, injection of miR-135a antagonist (AM135a) into the brain of AppTg mice was found to prevent neuronal apoptosis and improved the spatial learning ability. Together, our findings demonstrate a critical function for the astrocytic CEBPD, and point to miR-135a antagonist as an attractive therapeutic target for the treatment of Alzheimer's disease.
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 701, Taiwan.
authors.forename: Yu-Yi
authors.initials: YY
authors.lastname: Chu
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan.|Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, 110, Taiwan.
authors.forename: Chiung-Yuan
authors.initials: CY
authors.lastname: Ko
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, 701, Taiwan.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, 701, Taiwan.
authors.forename: Shao-Ming
authors.initials: SM
authors.lastname: Wang
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, 701, Taiwan.|Department of Pharmacology, National Cheng Kung University, Tainan, 701, Taiwan.
authors.forename: Po-Wu
authors.initials: PW
authors.lastname: Gean
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, 701, Taiwan.|Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan, 701, Taiwan.
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Kuo
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 701, Taiwan. wwwjm4721@yahoo.com.tw.|Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, 701, Taiwan. wwwjm4721@yahoo.com.tw.|Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan, 701, Taiwan. wwwjm4721@yahoo.com.tw.|Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, 701, Taiwan. wwwjm4721@yahoo.com.tw.|Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan. wwwjm4721@yahoo.com.tw.
authors.forename: Ju-Ming
authors.initials: JM
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000070416:Antagomirs / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000071446:Neuronal Outgrowth / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D065853:Spatial Learning / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D020413:3' Untranslated Regions; D000070416:Antagomirs; C544965:MIRN135 microRNA, human; D035683:MicroRNAs; C549289:Mirn135 microRNA, mouse; D051743:CCAAT-Enhancer-Binding Protein-delta
keywords: Neuroinflammation; Neuronal viability; Neuroprotective factor; Spatial learning ability; miR-135a