miR-34a knockout attenuates cognitive deficits in APP/PS1 mice through inhibition of the amyloidogenic processing of APP. Jian Chongdong,Lu Mengru,Zhang Zhao,Liu Long,Li Xianfeng,Huang Fang,Xu Ning,Qin Lina,Zhang Qian,Zou Donghua Life sciences The noncoding miRNA-34a (miR-34a) is involved in Alzheimer's disease (AD) pathologenesis and shows potential for application as a biomarker for early diagnosis and intervention. Here, we established miR-34a knockout mice in an APP/PS1 background (APP/PS1-miR-34a KO mice) by crossbreeding miR-34a mice with APP/PS1 mice. We then investigated cognitive impairment and related pathologies. The results showed that the level of miR-34a was increased at about 6months in APP/PS1 mice, consistent with the increase in amyloid β (Aβ), and cognitive function was significantly improved in mice when miR-34a was knocked out in 9-month-old and 12-month-old mice, indicating that miR-34a is a potential candidate for determining the progression of AD. Furthermore, we assessed the processing of amyloid precursor protein (APP) and the results suggest that cognitive improvement by miR-34a knock out was mainly triggered by depression of γ-secretase activity, without affecting β- and α-secretase activities, indicating that miR-34a plays an important role in AD pathology, mainly by inhibiting the amyloidogenic processing of APP, without altering the non-amyloidogenic processing of APP. 10.1016/j.lfs.2017.05.023

Neuroprotective effect of salidroside against central nervous system inflammation-induced cognitive deficits: A pivotal role of sirtuin 1-dependent Nrf-2/HO-1/NF-κB pathway. Xu Ning,Huang Fang,Jian Chongdong,Qin Lina,Lu Fang,Wang Yimei,Zhang Zhao,Zhang Qian Phytotherapy research : PTR Central nervous system (CNS) inflammation occurs in cognitive dysfunctions, but the underlying mechanisms remain unclear. Here, we investigated the role of sirtuin 1 (SIRT1) and salidroside in CNS inflammation-induced cognitive deficits model. In vivo, CNS inflammation was initiated by a single intracerebroventricular injection of lipopolysaccharide (LPS). The levels of inflammatory cytokines and the capability of free radial scavenging were determined after the LPS challenge. In vivo, salidroside and nicotinamide, a SIRT1 inhibitor, were used in PC12 cell. Of note, with the treatment of salidroside, LPS-induced learning and memory impairments were effectively improved. Salidroside also remarkably inhibited the inflammatory cytokines, up-regulated the concentration of superoxide dismutase and inhibited the vitalities of malondialdehyde in serum, hippocampus, and cell supernatant. Besides, the expression of Sirt1, Nrf-2, HO-1, Bax, Bcl-2, caspase-9, and caspase-3 and the phosphorylation of AMPK, NF-κBp65, and IκBα were increased accompanying with the LPS-induced cognitive impairments, which were significantly suppressed by salidroside treatment. In PC12 cell model, nicotinamide significantly abrogated the beneficial effects of salidroside, as indicated by the antioxidant, anti-inflammatory, and antiapoptosis signaling. Together, our results showed that salidroside may be a novel therapy drug in neurodegenerative diseases, and the protective effect was involved in SIRT1-dependent Nrf-2/HO-1/NF-κB pathway. 10.1002/ptr.6335

Association between promoter DNA methylation and gene expression in the pathogenesis of ischemic stroke. Deng Guo-Xiong,Xu Ning,Huang Qi,Tan Jin-Yue,Zhang Zhao,Li Xian-Feng,Wei Jin-Ru Aging To assess DNA methylation sites as well as gene expression related to ischemic stroke (IS) and comprehensively reveal their correlation and possible pathological mechanisms, we implemented (1) genome-wide DNA methylation profiling from the GEO repository related to IS with and without symptoms; (2) identification of differentially methylation positions (DMPs) and genes (DMGs), functional enrichment analysis along with DMG regulatory network construction; (3) validation tests of 2 differential methylation positions of interest as well as analogous gene expression in other datasets and in IS patients and controls; and (4) correlation analysis of DNA methylation and mRNA expression data. In total, 870 DMPs were physically located within 693 DMGs. After disease ontology (DO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, gene ontology (GO), protein-protein interaction (PPI) network construction as well as module analysis, HLA-DRB1 and HLA-DQB1 were identified. Their expression was validated in 4 other datasets but was significant in only 1, and the expression was lower in the IS group ( < 0.05). After validation in IS patients and controls, we found that these two genes showed more hypermethylation and lower expression levels in the IS group ( < 0.001). The methylation of genes was negatively associated with their expression ( < 0.05). The current study recognized a connection among DNA methylation and gene expression and emphasized the prominence of HLA-DRB1 and HLA-DQB1 in IS pathogenesis. 10.18632/aging.102278