Alzheimer's disease (AD) and cancer have inverse relationship in many aspects. Some tumor suppressors, including miR‐34c, are decreased in cancer but increased in AD. The upstream regulatory pathways and the downstream mechanisms of miR‐34c in AD remain to be investigated. The expression of miR‐34c was detected by RT–qPCR in oxidative stressed neurons, hippocampus of SAMP8 mice, or serum of patients with amnestic mild cognitive impairment (aMCI). Dual luciferase assay was performed to confirm the binding sites of miR‐34c in its target mRNA. The Morris water maze (MWM) was used to evaluate learning and memory in SAMP8 mice administrated with miR‐34c antagomir (AM34c). Golgi staining was used to evaluate the synaptic function and structure. The dramatically increased miR‐34c was mediated by ROS‐JNK‐p53 pathway and negatively regulated synaptotagmin 1 (SYT1) expression by targeting the 3′‐untranslated region (3′‐UTR) of syt1 in AD. The expression of SYT1 protein was reduced by over expression of miR‐34c in the HT‐22 cells and vice versa. Administration of AM34c by the third ventricle injection or intranasal delivery markedly increased the brain levels of SYT1 and ameliorated the cognitive function in SAMP8 mice. The serum miR‐34c was significantly increased in patients with aMCI and might be a predictive biomarker for diagnosis of aMCI. These results indicated that increased miR‐34c mediated synaptic and memory deficits by targeting SYT1 through ROS‐JNK‐p53 pathway and the miR‐34c/SYT1 pathway could be considered as a promising novel therapeutic target for patients with AD.

MicroRNAs (miRNAs), a class of small, non-coding RNA molecules with gene regulatory functions, have emerged to play a critical role in the pathogenesis of a variety of diseases. Recently, circulating miRNAs have been reported as potential biomarkers

The therapeutic effect of stroke is hampered by the lack of neuroprotective drugs against ischemic insults beyond the acute phase. Carnitine plays important roles in mitochondrial metabolism and in modulating the ratio of coenzyme A (CoA)/acyl-CoA. Here, we investigate the neuroprotective effects of l-carnitine (LC) and Acetyl-l-carnitine (ALC) pre-treatment on ischemic insults under the same experimental conditions. We used a transient middle cerebral artery occlusion (MCAO) model to evaluate the protective roles of LC and ALC in acute focal cerebral ischemia in vivo and to understand the possible mechanisms using model of PC12 cell cultures in vitro. Results showed that ALC, but not LC, decreased infarction size in SD rats after MCAO in vivo. However, both LC and ALC pretreatment reduced oxygen-glucose deprivation (OGD)-induced cell injury and decreased OGD-induced cell apoptosis and death in vitro; at the same time, both of them increased the activities of super oxide dismutase (SOD) and ATPase, and decreased the concentration of malondialdehyde (MDA) in vitro. Thus, our findings suggested that LC and ALC pre-treatment are highly effective in the prevention of neuronal cell against ischemic injury in vitro, however, only ALC has the protective effect on neuronal cell injury after ischemia in vivo.

Oxidative stress plays a critical role in the etiology and pathogenesis of neurodegenerative disorders, and the molecular mechanisms that control the neuron response to ROS have been extensively studied. However, the oxidative stress-effect on miRNA expression in hippocampal neurons has not been investigated, and little is known on the effect of ROS-modulated miRNAs on cell function. In this study, H₂O₂ was used to stimulate the mouse primary hippocampal neurons to develop an oxidative stress cell model. The alterations of miRNAs expression were detected by microarray analysis and five miRNAs were validated by real-time RT-PCR. The bioinformatic analysis of deregulated miRNAs was performed to determine their potential roles in the pathogenesis of neurological disorders. We found that H₂O₂ mediated a total of 101 deregulated miRNAs, which mainly took part in the regulation of the MAPK pathway. Among them, miR-135b and miR-708 were up-regulated significantly and their targets were predicted to be involved in DNA recombination, protein ubiquitination, protein autophosphorylation and development of neurons. These results demonstrated that oxidative stress alters the miRNA expression profile of hippocampal neurons, and the deregulated miRNAs might play a potential role in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease (AD).

Epigenetic aberrations have been identified as biomarkers to predict the risk of Alzheimer’s disease (AD). This study aimed to evaluate whether altered DNA methylation status of BDNF promoter could be used as potential epigenetic biomarkers for predicting the progression from amnestic mild cognitive impairment (aMCI) to AD. A total of 506 aMCI patients and 728 cognitively normal controls were recruited in the cross-sectional analyses. Patients ( n = 458) from aMCI cohort were classified into two groups after 5-year follow-up: aMCI-stable group ( n = 330) and AD-conversion group ( n = 128). DNA methylation of BDNF promoter was detected by bisulfite-PCR amplification and pyrosequencing. The DNA methylation levels of CpG1 and CpG2 in promoter I and CpG5 and CpG6 in promoter IV of BDNF gene were significantly higher in the aMCI group than in the control group at baseline and also were increased in the conversion group compared with the non-conversion group at 5-year follow up time point. CpG5 in BDNF promoter IV had the highest AUC of 0.910 (95% CI: 0.817–0.983, p < 0.05). Kaplan-Meier analysis showed a significant AD conversion propensity for aMCI patients with high methylation levels of CpG5 ( HR = 1.96, 95% CI: 1.07–2.98, p < 0.001). Multivariate Cox regression analysis revealed elevated methylation status of CpG5 was a significant independent predictor for AD conversion ( HR = 3.51, p = 0.013). These results suggest that elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to AD.