title: MiR-299-5p regulates apoptosis through autophagy in neurons and ameliorates cognitive capacity in APPswe/PS1dE9 mice.
abstract: Abnormalities of autophagy can result in neurodegenerative disorders such as Alzheimer's disease (AD). Nevertheless, the regulatory mechanisms of autophagy in AD are not well understood. Here, we describe our findings that microRNA (miR)-299-5p functions as an autophagy inhibitor by suppressing Atg5 and antagonizing caspase-dependent apoptosis. We observed decreased levels of miR-299-5p both in primary neurons under conditions of starvation and in hippocampi of APPswe/PS1dE9 mice. Additionally, low levels of miR-299-5p were observed in cerebrospinal fluid of AD patients. MiR-299-5p treatment resulted in attenuation of Atg5 and autophagy in primary neurons from APPswe/PS1dE9 mice, N2a cells and SH-SY5Y cells, whereas antagomiR-299-5p enhanced autophagy. Atg5 was verified as a direct target of miR-299-5p by dual luciferase reporter assays. Furthermore, transfection of miR-299-5p into primary hippocampal neurons caused the attenuation of caspase-mediated apoptosis, which was reversed upon starvation-induced autophagy. Inhibition of autophagy by shRNA knockdown of LC3β reduced apoptotic neuron death induced by antagomiR-299-5p. Injection of agomiR-299-5p into the cerebral ventricles of AD mice inhibited both autophagy and apoptosis and also improved the cognitive performance of mice. Overall, our results suggest that miR-299-5p modulates neuron survival programs by regulating autophagy. Thus, miR-299-5p serves as a potential neuroprotective factor in AD.
authors.affiliation: Clinical Laboratory of Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China.
authors.forename: Yueqi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Clinical Laboratory of Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China.
authors.forename: Chengeng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Clinical Laboratory of Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China.
authors.forename: Jinling
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medical Laboratory of Beijing Children's Hospital, Capital Medical University, Beijing 100053, P.R. China.
authors.forename: Qiliang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Clinical Laboratory of Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ping
authors.affiliation: Clinical Laboratory of Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China.
authors.forename: Shichao
authors.initials: S
authors.lastname: Gao
authors.affiliation: Clinical Laboratory of Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China.
authors.forename: Peichang
authors.initials: P
authors.lastname: Wang
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D003072:Cognition Disorders / Q000517:prevention & control*; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D016564:Amyloid beta-Protein Precursor; C000617415:MIRN299 microRNA, mouse; D035683:MicroRNAs; D053764:Presenilin-1