How iron is delivered to the CNS for myelination is not well understood. We assessed whether astrocytes can provide iron to cells in the CNS for remyelination. To study this we generated a conditional deletion of the iron efflux transporter ferroportin (Fpn) in astrocytes, and induced focal demyelination in the mouse spinal cord dorsal column by microinjection of lysophosphatidylcholine (LPC). Remyelination assessed by electron microscopy was reduced in astrocyte-specific Fpn knock-out mice compared with wild-type controls, as was proliferation of oligodendrocyte precursor cells (OPCs). Cell culture work showed that lack of iron reduces the ability of microglia to express cytokines (TNF-α and IL-1β) involved in remyelination. Furthermore, astrocytes in culture express high levels of FGF-2 in response to IL-1β, and IGF-1 in response to TNF-α stimulation. FGF-2 and IGF-1 are known to be important for myelination. Reduction in IL-1β and IGF-1 were also seen in astrocyte-specific Fpn knock-out mice after LPC-induced demyelination. These data suggest that iron efflux from astrocytes plays a role in remyelination by either direct effects on OPCs or indirectly by affecting glial activation.
"Iron accumulation in macrophages in SCI and EAE is also thought to be mediated via hepcidin-mediated loss of ferroportin (Rathore et al., 2008; Zarruk et al., 2015). Iron is required for cell proliferation and tissue repair, and in the CNS it is also required for remyelination (Schulz et al., 2012). Iron accumulation in macrophages in the injured spinal cord leads to increased TNF expression in these cells and free radical generation in vivo (Kroner et al., 2014). "
"It has been known for many years that astrocytes secrete promyelinating factors including cytokine leukemia inhibitory factor that promotes the myelinating activity of oligodendrocytes 42. Therefore, astrocytes have an important role in stimulating oligodendricytes to produce myelin for remyelination 43. In an attempt to gain a better understanding of the interaction between astrocytes and oligodendrocyte-based remyelination, we performed double immunostanning of GFAP and CNPase. "
[Show abstract][Hide abstract] ABSTRACT: The long-term impacts of cerebral ischemia and diabetic ischemia on astrocytes and oligodendrocytes have not been defined. The objective of this study is to define profile of astrocyte and changes of myelin in diabetic and non-diabetic rats subjected to focal ischemia.
Focal cerebral ischemia of 30-min duration was induced in streptozotocin-induced diabetic and vehicle-injected normoglycemic rats. The brains were harvested for immunohistochemistry of glial fibrillary acidic protein (GFAP) and 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) at various reperfusion endpoints ranging from 30 min up to 28 days. The results showed that activate astrocytes were observed after 30 min and peaked at 3 h to 1 day after reperfusion in ischemic penumbra, and peaked at 7 days of reperfusion in ischemic core. Diabetes inhibited the activation of astrocytes in ischemic hemisphere. Demyelination occurred after 30 min of reperfusion in ischemic core and peaked at 1 day. Diabetes caused more severe demyelination compared with non-diabetic rats. Remyelination started at 7 days and completed at 14 and 28 days in ischemic region. Diabetes inhibited the remyelination processes. It is concluded that ischemia activates astrocytes and induces demyelination. Diabetes inhibits the activation of astrocytes, exacerbates the demyelination and delays the remyelination processes. These may contribute to the detrimental effects of hyperglycemia on ischemic brain damage.
International journal of biological sciences 02/2013; 9(2):190-9. DOI:10.7150/ijbs.5844 · 4.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 2012 has been another year where multiple large scale clinical trials for Alzheimer's disease (AD) have failed to meet their clinical endpoints. With the social and financial burden of this disease increasing every year, the onus is now on the field of AD researchers to investigate alternative ideas in order to deliver outcomes for patients. While several major clinical trials targeting Aβ have failed, three smaller clinical trials targeting metal interactions with Aβ have all shown benefit for patients. Here we review the genetic, pathological, biochemical and pharmacological evidence that underlie the metal hypothesis of AD. The AD-affected brain suffers from metallostasis, or, fatigue of metal trafficking resulting in redistribution of metals into inappropriate compartments. The metal hypothesis is built upon the triad of transition elements: iron, copper, and zinc. The hypothesis has matured from early investigations showing amyloidogenic and oxidative stress consequences of these metals; recently, disease related proteins: APP, tau and presenilin, have been shown to have major roles in metal regulation, which provides insight into the pathway of neurodegeneration in AD and illuminates potential new therapeutic avenues.
Free Radical Biology and Medicine 11/2012; 62. DOI:10.1016/j.freeradbiomed.2012.10.558 · 5.74 Impact Factor
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