Affiliations: [a]
Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, P.R. China | [b]
Department of CT Diagnosis, The Second Affiliated Hospital of Harbin Medical University, Harbin, P.R. China | [c]
Department of Rehabilitation Medicine, The Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, P.R. China
Correspondence:
[*]
Corresponding authors: Shurong Duan and Jingkun Zhao, Department of Neurology, The First Affiliated Hospital of Harbin Medical University, No. 23, Postal Street, Nangang District, Harbin, 150001, P.R. China. Tel.: +86 451 85556000. E-mails: duanshuronghyd@163.com (S.D.) and zhaojingkunhyd@163.com (J.Z.).
Abstract: Background:Growing evidence has demonstrated that long non-coding RNAs (lncRNAs) play a critical role in Alzheimer’s disease (AD), which is characterized by sustained mitochondrial dysfunction, inevitable memory loss, and cognitive decline. However, the potential function of lncRNAs MIR600 Host Gene (MIR600HG) in AD remains unanswered. Objective:Our study aimed to investigate the role of MIR600HG and its related molecular mechanism in AD. Methods:The expression of MIR600HG was examined by qRT-PCR. The MIR600HG interacting proteins were identified by RNA pull-down assay and mass spectrometry and verified by RNA immunoprecipitation. Immunofluorescence staining was applied to examine the colocalization of PINK1 and NEDD4L. The PINK1 level and the activation of autophagy were detected by immunoblotting. Morris water maze test was performed to evaluate cognitive decline in AD mice model. Results:MIR600HG expression was elevated during aging in two different types of AD transgenic mouse models. Next, we found that increased MIR600HG directly interact with NEDD4L, which promoted PINK1 ubiquitination and degradation, and as well as autophagy activation. Additionally, MIR600HG promoted Aβ production and suppressed Cytochrome C Oxidase activity. Administration of AAV-shMIR600HG restored the Cytochrome C Oxidase activity and inhibited Aβ production. Furthermore, PINK1 overexpression or MIR600HG knockdown significantly ameliorated the cognitive impairment in APP/PS1 mice. PINK1 depletion recovered the spatial memory defect in the AAV-shMIR600HG injected APP/PS1 mice. Conclusion:MIR600HG was increased in AD and promoted AD pathogenesis. Targeting MIR600HG significantly improved cognitive function in AD mice, which could pave the way for exciting new avenues in AD therapeutic strategy research.
