Novel Plasma miRNAs as Biomarkers and Therapeutic Targets of Alzheimer’s Disease at the Prodromal Stage

Article type: Research Article

Authors: He, Haining^{a; b; 1} | Liu, An^{a; c; 1} | Zhang, Wei^{a; c; 1} | Yang, Huanqing^{a; c} | Zhang, Minmin^d | Xu, Hua^{a; c} | Liu, Yuanyuan^{a; c} | Hong, Bo^{a; c} | Yan, Feng^{a; c} | Yue, Ling^{a; c} | Wang, Jinghua^{a; c} | Xiao, Shifu^{a; c; *} | Xie, Zuoquan^{d; *} | Wang, Tao^{a; c; *}

Affiliations: [a] Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China | [b] Department of Psychiatry, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China | [c] Alzheimer’s Disease and Related Disorders Center, Shanghai Jiao Tong University, Shanghai, China | [d] State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

Correspondence: [*] Correspondence to: Tao Wang and Shifu Xiao, 600th South Wanping Road, Xuhui District, Shanghai, China. E-mail: wtshhwy@163.com. (Tao Wang), E-mail: xiaoshifu@msn.com. (Shifu Xiao) and Zuoquan Xie, 555th Zuchongzhi Road, Pudong District, Shanghai, China. E-mail: zqxie@simm.ac.cn.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Amnestic mild cognitive impairment (aMCI) is a prodromal stage of Alzheimer’s disease (AD) involving imbalanced beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). MicroRNAs (miRNAs) are associated with AD. Objective:This study aimed to investigated whether plasma miRNAs can predict prodromal AD or are associated with AD pathology. Methods:Participants in the discovery set (n = 10), analysis set (n = 30), and validation set (n = 80) were screened from the China Longitudinal Aging Study. RNA was extracted from the participants’ plasma. Microarray sequencing provided miRNA profiles and differentially expressed miRNAs (DEmiRNAs) in the discovery set included patients with 18F-Flutemetamol positron emission tomography scan-confirmed aMCI. Potential biomarkers were screened in the analysis set. The predict capability of candidate miRNAs was assessed in the validation set. Candidate miRNAs modulation of BACE1 expression was explored in rat and human hippocampal neurons in vitro. Results:We verified 46 significant DEmiRNAs between the aMCI and NC groups (p < 0.05), among which 33 were downregulated. In the analysis set, miR-1185-2-3p, miR-1909-3p, miR-22-5p, and miR-134-3p levels decreased significantly in the aMCI group. These miRNAs and previously identified miR-107 were selected as potential biomarkers. A prediction model comprising these five miRNAs showed outstanding accuracy (81.25%) to discriminate aMCI at cut-off value of 0.174. Except for miR-134-3p, the other four miRNAs significantly suppressed Bace1 expression in rat hippocampal neurons in vitro. BACE1 modulation of miR-1185-2-3p, miR-1909-3p, and miR-134-3p was confirmed in human hippocampal neurons in vitro. Conclusion:A predictive model consisting of five BACE1-related plasma miRNAs could be a novel biomarker for aMCI.

Keywords: Alzheimer’s disease, biomarkers, microRNAs, mild cognitive impairment

DOI: 10.3233/JAD-210307

Journal: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 779-790, 2021