Advanced glycation end products induce Aβ1–42 deposition and cognitive decline through H19/miR-15b/BACE1 axis in diabetic encephalopathy

Abstract

ObjectiveDiabetic encephalopathy (DE), a chronic complication of diabetes, is characterized by decline of cognitive function. The molecular mechanism of DE remains unclear. The purpose of this study is to evaluate the roles of advanced glycation end products (AGEs) in the pathogenesis of DE and investigate its underlying mechanisms in this process. MethodsDE rats were developed by incorporating a high-fat diet and streptozotocin injection followed by the Morris Water Maze test. HT-22 cells were used to mimic the in vitro neuronal injuries of DE. Expression levels of long non-coding RNA H19, miR-15b and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) mRNA in the hippocampus of DE rats or HT-22 cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The levels of BACE1 proteins were analyzed by western blotting or immunohistochemical staining. The contents of Aβ1–42 in supernatant of the cell culture were analyzed by enzyme-linked immu-nosorbent assay (ELISA). The relationship between H19 or BACE1 and miR-15b was verified with dual-luciferase reporter assay. ResultsWe found that the accumulation of Aβ1–42 and the phosphorylation of Tau (Ser404) were increased in the hippocampus CA3 regionof DE rats. MiR-15b was downregulated while H19 and BACE1 were upregulated in the hippocampus CA3 regionof DE rats and AGEs-treated HT-22 cells. The expression of BACE1 protein was negatively regulated by miR-15b at the post-transcriptional level in HT-22 cells. In vivo, administration of miR-15b mimics by the intranasal delivery markedly decreased the BACE1 protein in hippocampal CA3 region and improved the cognitive decline in DE rats. Besides, the luciferase activity assay confirmed the binding site of miR-15b to both the 3′-untranslated region (3′-UTR) of BACE1 mRNA and H19. Then, miR-15b inhibitor reversed H19 knockdown-mediated decrease of Aβ1–42 level in AGEs-treated HT-22 cells. ConclusionThese results suggested that AGEs induced Aβ1–42 deposition andcognitive decline through H19/miR-15b/ BACE1 axis in DE.