Advanced Glycosylation End Products Induced Synaptic Deficits and Cognitive Decline Through ROS-JNK-p53/miR-34c/SYT1 Axis in Diabetic Encephalopathy

Article type: Research Article

Authors: Zhang, Rui^{a; b; c; 1} | Jiang, Lei^{a; b; c; 1} | Li, Guofeng^d | Wu, JingJing^e | Tian, Pei^{a; b; c} | Zhang, Di^{a; b; c} | Qin, Yushi^{a; b; c} | Shi, Zhongli^{a; b; c} | Gao, ZhaoYu^{a; b; c} | Zhang, Nan^{a; b; c} | Wang, Shuang^c | Zhou, Huimin^{b; c; f; *} | Xu, Shunjiang^{a; b; c; *}

Affiliations: [a] Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China | [b] Hebei International Joint Research Center for Brain Science, Shijiazhuang, P. R. China | [c] Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China | [d] Hebei Center for Disease Control and Prevention, Shijiazhuang, P. R. China | [e] Clinical Laboratory, Cangzhou Central Hospital, Cangzhou, P. R. China | [f] Department of Endocrinology, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China

Correspondence: [*] Correspondence to: Shunjiang Xu and Huimin Zhou, Central Laboratory, The First Hospital of Hebei Medical University, No.89, Donggang Road, Shijiazhuang, 050031, P. R. China. Tel.: +86 311 8715 6463; Fax: +86 311 8715 6463; E-mails: sjxu66@hotmail.com, zhouhuimindoctor@163.com; ORCID: https://orcid.org/0000-0002-9441-3900 (Xu), https://orcid.org/0000-0002-3542-0625 (Zhang)

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

Abstract: Background:miR-34c has been found to be implicated in the pathological process of Alzheimer’s disease, diabetes, and its complications. Objective:To investigate the underlying mechanisms of miR-34c in the pathogenesis of diabetic encephalopathy (DE). Methods:Diabetes mellitus rats were developed by incorporating a high-fat diet and streptozotocin injection. Morris water maze test and novel object recognition test were used to assess the cognitive function of rats. Expression of miR-34c were detected by fluorescence in situ hybridization and qRT-PCR. Immunofluorescence and western blot were used to evaluate synaptotagmin 1 (SYT1) and AdipoR2 or other proteins. Golgi staining was performed to investigate dendritic spine density. Results:The increased miR-34c induced by advanced glycation end-products (AGEs) was mediated by ROS-JNK-p53 pathway, but not ROS-Rb-E2F1 pathway, in hippocampus of DE rats or in HT-22 cells. miR-34c negatively regulated the expression of SYT1, but not AdipoR2, in hippocampal neurons. miR-34c inhibitor rescued the AGE-induced decrease in the density of dendritic spines in primary hippocampal neurons. Administration of AM34c by the intranasal delivery increased the hippocampus levels of SYT1 and ameliorated the cognitive function in DE rats. The serum levels of miR-34c were increased in patients with DE comparing with normal controls. Conclusion:These results demonstrated that AGE-induced oxidative stress mediated increase of miR-34c through ROS-JNK-p53 pathway, resulting in synaptic deficits and cognitive decline by targeting SYT1 in DE, and the miR-34c/SYT1 axis could be considered as a novel therapeutic target for DE patients.

Keywords: Advanced glycation end products, diabetic encephalopathy, miRNA, P53 protein, synaptic deficits, synaptotagmin 1

DOI: 10.3233/JAD-215589

Journal: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 843-861, 2022