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Article type: Research Article
Authors: Zhou, Yajuna | Deng, Jiangshana | Chu, Xiulia | Zhao, Yuwua | Guo, Yongb; *
Affiliations: [a] Department of Neurology, Shanghai Jiao Tong University affiliated Sixth People’s Hospital, Shanghai, China | [b] Department of Critical Care Medicine, Shanghai Jiao Tong University affiliated Sixth People’s Hospital, Shanghai, China
Correspondence: [*] Correspondence to: Yong Guo, Department of Critical Care Medicine, Shanghai Jiao Tong University affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai 200233, China. Tel.: +86 2164369181; Fax: +86 2164701361; E-mail: [email protected].
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease prevalent in aged people, clinically characterized by progressive memory loss, behavioral and learning dysfunction, and cognitive deficits. The pathogenesis of AD is hallmarked by formation of amyloid-β peptide aggregates (Aβ) and intraneuronal neurofibrillary tangles (NFTs), which are induced by hyperphosphorylation of amyloid-β protein precursor and tau protein, respectively. The hyperphosphorylation is controlled by cyclin-dependent kinase-5 (CDK5), the aberrant activation of which is mediated by calpain (CAPN)-induced cleavage of p35 into p25. However, the regulation of CAPN in AD remains largely unknown. Here, we studied the post-transcriptional control of CAPN1 by microRNAs (miRNAs) in the setting of AD. We found that miR-124-3p, previously reported as a miRNA that was downregulated in AD, was a CAPN1-targeting miRNA that functionally inhibited the protein translation of CAPN1 in a human neural cell line, HCN-2. In vitro, transfection with miR-124-3p reduced the levels of CAPN1 protein, the cleavage of p35 into p25, and cell apoptosis dose-dependently in HCN-2 cells. Moreover, a significant inverse correlation was detected between the levels of miR-124-3p and CAPN1 in AD specimens. Furthermore, intracranial injection of adeno-associated virus expressing miR-124-3p into APP/PS1-AD mice significantly reduced Aβ deposition and significantly improved the AD-mouse behavior in the social recognition test and plus-maze discriminative avoidance task. Together, our data suggest that post-transcriptional control of calpain by miR-124-3p plays an essential role in the development of AD.
Keywords: Alzheimer’s disease, amyloid-β peptide aggregates, calpain 1, CDK5, miR-124-3p
DOI: 10.3233/JAD-181053
Journal: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 571-581, 2019
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