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

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.

Synaptotagmin-1 attenuated myocardial programmed necrosis and ischemia/reperfusion injury through the mitochondrial pathway

“…The burst release of ROS through prolonged mPTP opening results in dissipation of mitochondrial membrane potential, organelle swelling and rupture, mitochondrial dysfunction and cell death[8, 9,41]. Syt1 has been reported to be associated with oxidative stress regulation in glioma, neuron, and diabetic encephalopathy, but direct evidence is lacking [28][29][30]. Here we demonstrated that Syt1 was abundantly distributed in the mitochondria of cardiomyocytes.…”

“…Syt1-positive neurons exhibit more axonal varices which is a key feature of neuronal susceptibility to oxidative stress [29]. Both the mRNA and the protein levels of Syt1 were decreased during oxidative stress induced by advanced glycation end-products (AGEs) in diabetic encephalopathy [30]. Bioinformatics analysis suggests a strong correlation between Syt1 and oxidative stress [28].…”

Metabolic memory: mechanisms and diseases

“…369 In addition, miRNAs play important regulatory roles in metabolic memory-mediated neurodegenerative diseases. [370][371][372][373] For example, miR-132 is downregulated in hippocampal neurons in rats with diabetic encephalopathy, accompanied by upregulated glycogen synthase kinase (GSK)-3β and tau. miR-132 could alleviate the impairment of diabetic encephalopathy via inhibiting GSK-3β expression and attenuating Tau hyperphosphorylation.…”

Exploration of Polysaccharides from Phyllanthus emblica: Isolation, Identification, and Evaluation of Antioxidant and Anti-Glycolipid Metabolism Disorder Activities

“…Advanced glycosylation end products are usually produced by non-enzymatic glycosylation caused by hyperglycemia; they are a set of isomeric metabolites characterized by significant toxicity [7][8][9]. AGEs are difficult to remove in the body, are closely related to the occurrence and development of CVD, and are considered to be an important cause of microvascular complications and lipid mass spectrometry changes in diabetes [10].…”