Oligodendrocyte precursor cells (OPCs) account for 5% of the resident parenchymal central nervous system glial cells. OPCs are not only a back-up for the loss of oligodendrocytes that occurs due to brain injury or inflammation-induced demyelination (remyelination) but are also pivotal in plastic processes such as learning and memory (adaptive myelination). OPC differentiation into mature myelinating oligodendrocytes is controlled by a complex transcriptional network and depends on high metabolic and mitochondrial demand. Mounting evidence shows that OPC dysfunction, culminating in the lack of OPC differentiation, mediates the progression of neurodegenerative disorders such as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Importantly, neurodegeneration is characterised by oxidative and carbonyl stress, which may primarily affect OPC plasticity due to the high metabolic demand and a limited antioxidant capacity associated with this cell type. The underlying mechanisms of how oxidative/carbonyl stress disrupt OPC differentiation remain enigmatic and a focus of current research efforts. This review proposes a role for oxidative/carbonyl stress in interfering with the transcriptional and metabolic changes required for OPC differentiation. In particular, oligodendrocyte (epi)genetics, cellular defence and repair responses, mitochondrial signalling and respiration, and lipid metabolism represent key mechanisms how oxidative/carbonyl stress may hamper OPC differentiation in neurodegenerative disorders. Understanding how oxidative/carbonyl stress impacts OPC function may pave the way for future OPC-targeted treatment strategies in neurodegenerative disorders.

Transporters in the ABCG family appear to be involved in the cellular excretion of cholesterol and other sterols in a cell‐ and tissue‐specific fashion. Overexpression of ATP‐binding cassette transporters G1 (Abcgl) and G4 (Abcg4) can promote cellular cholesterol efflux to high‐density lipoprotein (HDL), but the in vivo functions of Abcg4 are poorly understood. We used mice with knockouts of Abcgl or Abcg4 singly or together to further elucidate the function of these transporters. Abcg1 and Abcg4 are highly expressed in the brain and are found in both astrocytes and neurons. Whereas Abcgl ^_/_ or Abcg4 ^_/_ mice showed essentially normal levels of brain sterols, in Abcgl ^_/_ /Abcg4 ^_/_ mice, levels of several sterol intermediates in the cholesterol biosynthetic pathway, namely desmosterol, lathosterol, and lanosterol, as well as 27‐OH cholesterol, were increased 2‐ to 3‐fold. Overexpression of Abcgl or Abcg4 promoted efflux of desmosterol and cholesterol from cells to HDL, and combined deficiency of these transporters led to defective efflux and accumulation of these sterols in primary astrocytes. Consistent with defective efflux and sterol accumulation, cholesterol biosynthesis was reduced in Abcgl ^_/_ /Abcg4 ^_/_ astrocytes. The accumulation of desmosterol, a known liver‐X receptor (LXR) activator, was associated with increased expression of LXR target genes, including ATP‐binding cassette transporter Al, and increased apolipoprotein E secretion in Abcgl ^_/_ / Abcg4 ^_/_ astrocytes. Our findings provide the first in vivo demonstration of a role for Abcg4 in sterol efflux in the brain and show that Abcgl and Abcg4 have overlapping functions in astrocytes, promoting efflux of cholesterol, desmosterol, and possibly other sterol biosynthetic intermediates to HDL. Wang, N., Yvan‐Charvet, L., Lutjohann, D., Mulder, M., Vanmierlo, T., Kim, T.‐W., Tall, A. R ATP‐binding cassette transporters Gl and G4 mediate cholesterol and desmosterol efflux to HDL and regulate sterol accumulation in the brain. FASEB J. 22, 1073–1082 (2008)

BACKGROUND AND PURPOSE Strategies designed to enhance cerebral cAMP have been proposed as symptomatic treatments to counteract cognitive deficits. However, pharmacological therapies aimed at reducing PDE4, the main class of cAMP catabolizing enzymes in the brain, produce severe emetic side effects. We have recently synthesized a 3-cyclopentyloxy-4-methoxybenzaldehyde derivative, structurally related to rolipram, and endowed with selective PDE4D inhibitory activity. The aim of the present study was to investigate the effect of the new drug, namely GEBR-7b, on memory performance, nausea, hippocampal cAMP and amyloid-β (Aβ) levels. EXPERIMENTAL APPROACH To measure memory performance, we performed object recognition tests on rats and mice treated with GEBR-7b or rolipram. The emetic potential of the drug, again compared with rolipram, was evaluated in rats using the taste reactivity test and in mice using the xylazine/ketamine anaesthesia test. Extracellular hippocampal cAMP was evaluated by intracerebral microdialysis in freely moving rats. Levels of soluble Aβ peptides were measured in hippocampal tissues and cultured N2a cells by elisa. KEY RESULTS GEBR-7b increased hippocampal cAMP, did not influence Aβ levels and improved spatial, as well as object memory performance in the object recognition tests. The effect of GEBR-7b on memory was 3 to 10 times more potent than that of rolipram, and its effective doses had no effect on surrogate measures of emesis in rodents. CONCLUSION AND IMPLICATIONS Our results demonstrate that GEBR-7b enhances memory functions at doses that do not cause emesis-like behaviour in rodents, thus offering a promising pharmacological perspective for the treatment of memory impairment.

Dietary plant sterols and stanols as present in our diet and in functional foods are well-known for their inhibitory effects on intestinal cholesterol absorption, which translates into lower low-density lipoprotein cholesterol concentrations. However, emerging evidence suggests that plant sterols and stanols have numerous additional health effects, which are largely unnoticed in the current scientific literature. Therefore, in this review we pose the intriguing question "What would have occurred if plant sterols and stanols had been discovered and embraced by disciplines such as immunology, hepatology, pulmonology or gastroenterology before being positioned as cholesterol-lowering molecules?" What would then have been the main benefits and fields of application of plant sterols and stanols today? We here discuss potential effects ranging from its presence and function intrauterine and in breast milk towards a potential role in the development of non-alcoholic steatohepatitis (NASH), cardiovascular disease (CVD), inflammatory bowel diseases (IBD) and allergic asthma. Interestingly, effects clearly depend on the route of entrance as observed in intestinal-failure associated liver disease (IFALD) during parenteral nutrition regimens. It is only until recently that effects beyond lowering of cholesterol concentrations are being explored systematically. Thus, there is a clear need to understand the full health effects of plant sterols and stanols.

Oligodendrocytes provide metabolic and functional support to neuronal cells, rendering them key players in the functioning of the central nervous system. Oligodendrocytes need to be newly formed from a pool of oligodendrocyte precursor cells (OPCs). The differentiation of OPCs into mature and myelinating cells is a multistep process, tightly controlled by spatiotemporal activation and repression of specific growth and transcription factors. While oligodendrocyte turnover is rather slow under physiological conditions, a disruption in this balanced differentiation process, for example in case of a differentiation block, could have devastating consequences during ageing and in pathological conditions, such as multiple sclerosis. Over the recent years, increasing evidence has shown that epigenetic mechanisms, such as DNA methylation, histone modifications, and microRNAs, are major contributors to OPC differentiation. In this review, we discuss how these epigenetic mechanisms orchestrate and influence oligodendrocyte maturation. These insights are a crucial starting point for studies that aim to identify the contribution of epigenetics in demyelinating diseases and may thus provide new therapeutic targets to induce myelin repair in the long run.