miR-26b Mimic Inhibits Glioma Proliferation In Vitro and In Vivo Suppressing COX-2 Expression.

Glioma is the most common malignant tumor of the nervous system. Studies have shown the microRNA-26b (miR-26b)/cyclooxygenase-2 (COX-2) axis in the development and progression in many tumor cells. Our study aims to investigate the effect and mechanism of the miR-26b/COX-2 axis in glioma. Decreased expression of miR-26b with increased levels of COX-2 was found in glioma tissues compared with matched normal tissues. A strong negative correlation was observed between the level of miR-26b and COX-2 in 30 glioma tissues. The miR-26b was then overexpressed by transfecting a miR-26b mimic into U-373 cells. The invasive cell number and wound closing rate were reduced in U-373 cells transfected with miR-26b mimic. In addition, COX-2 siRNA enhanced the effect of miR-26b mimic in suppressing the expression of p-ERK1 and p-JNK. Finally, the in vivo experiment revealed that miR-26b mimic transfection strongly reduced the tumor growth, tumor volume, and expression of matrix metalloproteinase-2 (MMP-2) and MMP-9. Taken together, our research indicated a miR-26b/COX-2/ERK/JNK axis in regulating the motility of glioma in vitro and in vivo, providing a new sight for the treatment of glioma.

Amniotic Mesenchymal Stem Cells Decrease Aß Deposition and Improve Memory in APP/PS1 Transgenic Mice.

Transplantation of human amniotic mesenchymal stem cells (hAM-MSCs) seems to be a promising strategy for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, the clinical therapeutic effects of hAM-MSCs and their mechanisms of action in AD remain to be determined. Here, we used amyloid precursor protein (APP) and presenilin1 (PS1) double-transgenic mice to evaluate the effects of hAM-MSC transplantation on AD-related neuropathology and cognitive dysfunction. We found that hAM-MSC transplantation into the hippocampus dramatically reduced amyloid-ß peptide (Aß) deposition and rescued spatial learning and memory deficits in APP/PS1 mice. Interestingly, these effects were associated with increasing in Aß-degrading factors, elevations in activated microglia, and the modulation of neuroinflammation. Furthermore, enhanced hippocampal neurogenesis in the subgranular zone (SGZ) of the dentate gyrus (DG) and enhanced synaptic plasticity following hAM-MSC treatment could be another important factor in reversing the cognitive decline in APP/PS1 mice. Instead, the mechanism underlying the improved cognition apparently involves a robust increase in hippocampal synaptic density and neurogenesis that is mediated by brain-derived neurotrophic factor (BDNF). In conclusion, our data suggest that hAM-MSCs may be a new and effective therapy for the treatment of AD.

Lamotrigine attenuates deficits in synaptic plasticity and accumulation of amyloid plaques in APP/PS1 transgenic mice.

Hyperactivity and its compensatory mechanisms may causally contribute to synaptic and cognitive deficits in Alzheimer's disease (AD). Blocking the overexcitation of the neural network, with levetiracetam (LEV), a sodium channel blocker applied in the treatment of epilepsy, prevented synaptic and cognitive deficits in human amyloid precursor protein (APP) transgenic mice. This study has brought the potential use of antiepileptic drugs (AEDs) in AD therapy. We showed that the chronic treatment with lamotrigine (LTG), a broad-spectrum AED, suppressed abnormal spike activity, prevented the loss of spines, synaptophysin immunoreactivity, and neurons, and thus attenuated the deficits in synaptic plasticity and learning and memory in APP and presenilin 1 (PS1) mice, which express human mutant APP and PS1. In contrast with LEV, which failed to reduce the generation of amyloid ß, the chronic LTG treatment reduced the cleavage of APP by ß-secretase and thus the numbers and the size of amyloid plaques in the brains of APP and PS1 mice. Moreover, the levels of brain-derived neurotrophic growth factor (BDNF) and nerve growth factor (NGF) were enhanced in the brains of APP and PS1 mice by the chronic LTG treatment. Therefore, these observations demonstrate that LTG attenuates AD pathology through multiple mechanisms, including modulation of abnormal network activity, reduction of the generation of amyloid beta and upregulation of BDNF and NGF.

TDP-43 interaction with the intracellular domain of amyloid precursor protein induces p53-associated apoptosis.

TAR DNA-binding protein 43 (TDP-43), an essential pathological protein in both amyotrophic later sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), is expressed abnormally in Alzheimer's disease (AD). However, whether and how TDP-43 contributes the pathogenesis of AD remains unknown. We have shown here a colocalization between TDP-43 and the intracellular domain of APP (AICD) in the nucleus. Coimmunoprecipitation analysis showed an interaction between TDP-43 and AICD. Overexpression of TDP-43 in COS7 cells enhanced the transactivation of AICD in an APP-Gal4 luciferase reporter system. Real-time PCR analysis showed that cotransfection of TDP-43 and AICD in HEK293 cells increased P53 mRNA levels compared to either TDP-43-transfected or AICD-transfected cells. Moreover, cotransfection of TDP-43 and AICD in either N2a or COS7 cells showed increased numbers of apoptotic cells compared to either TDP-43-transfected or AICD-transfected cells, indicating that TDP-43 enhances AICD-mediated apoptosis in N2a or COS7 cells. Thus, TDP-43 may play a role in AD pathology through interaction with AICD.