Prolonged myelin deficits contribute to neuron loss and functional impairments after ischaemic stroke.

Ischaemic stroke causes neuron loss and long-term functional deficits. Unfortunately, effective approaches to preserving neurons and promoting functional recovery remain unavailable. Oligodendrocytes, the myelinating cells in the CNS, are susceptible to oxygen and nutrition deprivation and undergo degeneration after ischaemic stroke. Technically, new oligodendrocytes and myelin can be generated by the differentiation of oligodendrocyte precursor cells (OPCs). However, myelin dynamics and their functional significance after ischaemic stroke remain poorly understood. Here, we report numerous denuded axons accompanied by decreased neuron density in sections from ischaemic stroke lesions in human brain, suggesting that neuron loss correlates with myelin deficits in these lesions. To investigate the longitudinal changes in myelin dynamics after stroke, we labelled and traced pre-existing and newly-formed myelin, respectively, using cell-specific genetic approaches. Our results indicated massive oligodendrocyte death and myelin loss 2 weeks after stroke in the transient middle cerebral artery occlusion (tMCAO) mouse model. In contrast, myelin regeneration remained insufficient 4 and 8 weeks post-stroke. Notably, neuronal loss and functional impairments worsened in aged brains, and new myelin generation was diminished. To analyse the causal relationship between remyelination and neuron survival, we manipulated myelinogenesis by conditional deletion of Olig2 (a positive regulator) or muscarinic receptor 1 (M1R, a negative regulator) in OPCs. Deleting Olig2 inhibited remyelination, reducing neuron survival and functional recovery after tMCAO. Conversely, enhancing remyelination by M1R conditional knockout or treatment with the pro-myelination drug clemastine after tMCAO preserved white matter integrity and neuronal survival, accelerating functional recovery. Together, our findings demonstrate that enhancing myelinogenesis is a promising strategy to preserve neurons and promote functional recovery after ischaemic stroke.

Brain region-specific myelinogenesis is not directly linked to amyloid-ß in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is characterized by aggregating amyloid beta-protein (Aß). Recent evidence has shown that insufficient myelinogenesis contributes to AD-related functional deficits. However, it remains unclear whether Aß, in either plaque or soluble form, could alter myelinogenesis in AD brains. By cell-lineage tracing and labeling, we found both myelinogenesis and Aß deposits displayed a region-specific pattern in the 13-month-old APP/PS1 transgenic mouse brains. Aß plaques cause focal demyelination, but only about 15% Aß plaques are closely associated with newly formed myelin in the APP/PS1 brains. Further, the Aß plaque total area and the amount of new myelin are not linearly correlated across different cortical regions, suggesting that Aß plaques induce demyelination but may not exclusively trigger remyelination. To understand the role of soluble Aß in regulating myelinogenesis, we chose to observe the visual system, wherein soluble Aß is detectable but without the presence of Aß plaques in the APP/PS1 retina, optic nerve, and optic tract. Interestingly, newly-formed myelin density was not significantly altered in the APP/PS1 optic nerves and optic tracts as compared to the wildtype controls, suggesting soluble Aß probably does not change myelinogenesis. Further, treatment of purified oligodendrocyte precursor cells (OPCs) with soluble Aß (oligomers) for 48 h did not change the cell densities of MBP positive cells and PDGFRα positive OPCs in vitro. Consistently, injection of soluble Aß into the lateral ventricles did not alter myelinogenesis in the corpus callosum of NG2-CreErt; Tau-mGFP mice significantly. Together, these findings indicate that the region-dependent myelinogenesis in AD brains is not directly linked to Aß, but rather probably a synergic result in adapting to AD pathology.

DNA Hypermethylation Induced by L-Methionine Leads to Oligodendroglial and Myelin Deficits and Schizophrenia-Like Behaviors in Adolescent Mice.

Increasing evidence has demonstrated that in addition to dysfunction of neuronal circuitry, oligodendroglial dysfunction and/or disruption of white matter integrity are found in the brains of patients with schizophrenia. DNA methylation, a well-established risk factor for schizophrenia, has been demonstrated to cause neuronal dysfunction; however, whether dysregulation of DNA methylation contributes to oligodendroglial/myelin deficits in the pathogenesis of schizophrenia remains unclear. In the present study, by using L-methionine-treated mice, we confirmed that mice with DNA hypermethylation exhibited an anxious phenotype, impaired sociability, and sensorimotor gating deficits. Notably, DNA hypermethylation in oligodendroglial cells led to dysregulation of multiple oligodendroglia-specific transcription factors, which indicated disruption of the transcriptional architecture. Furthermore, DNA hypermethylation caused a reduction of oligodendroglial lineage cells and myelin integrity in the frontal white matter of mice. Taken together, these results indicate that DNA hypermethylation leads to oligodendroglial and/or myelin deficits, which may, at least in part, contribute to schizophrenia-like behaviors in mice. This study provides new insights into the possibility that precise modulation of DNA methylation status in oligodendroglia could be beneficial for the white matter pathology in schizophrenia.

Altered patterns of gene expression distinguishing unruptured abdominal aortic aneurysms from ruptured ones: comprehensive analysis of inflammatory factors.

The purpose of this study was to profile altered patterns of gene expression that characterize abdominal aortic aneurysm and to compare these patterns between different conditions, unruptured (URA) and ruptured (RA). Full-thickness aortic wall tissues were obtained from patients during surgical repair of abdominal aortic aneurysm, including unruptured (n=29) and ruptured (n=11). RNA, protein and blood samples were prepared for each specimen, and differential levels of gene expression between unruptured and ruptured abdominal aortic tissues were assessed by immunohistochemistry, RT-qPCR and ELISA assays. Biochemical assay showed that triglyceride (TG), total cholesterol (TC) and low density lipoprotein (LDL) concentration in the peripheral blood of URA and UA patients with large size of aneurysm (>5 cm) was significantly increased compared with those with small size of aneurysm (3-5 cm). Of 7 genes examined, TRPV1, CAM, TNF-α, IL-6, MCP-1 and VCAM were significantly increased in RA patients compared with URA patients, which also showed markedly increased expression in large size of aneurysm, with TRPV1 and CAM exception in RA patients. Only PPARδ expression observed decrease in RA patients with larger size of aneurysm. Taken together, URA and RA exhibit distinct patterns of gene expression, with most alterations being unique to this disease. Abdominal aortic aneurysm arising in different sizes of aneurysm is thus characterized by a high degree of molecular heterogeneity, reflecting different pathophysiologic mechanisms.