Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination

The efficiency of central nervous system remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study, we show that expression of genes involved in the retinoid X receptor pathway are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages using a combination of in vivo and in vitro approaches. Disruption of retinoid X receptor function in young macrophages, using the antagonist HX531, mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα (Rxra) knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentally-induced demyelination. Alternatively, retinoid X receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in multiple sclerosis patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. These results reveal the retinoid X receptor pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.

The role of the cerebral cortex in postural responses to externally induced perturbations

The ease with which we avoid falling down belies a highly sophisticated and distributed neural network for controlling reactions to maintain upright balance. Although historically these reactions were considered within the sub cortical domain, mounting evidence reveals a distributed network for postural control including a potentially important role for the cerebral cortex. Support for this cortical role comes from direct measurement associated with moments of induced instability as well as indirect links between cognitive task performance and balance recovery. The cerebral cortex appears to be directly involved in the control of rapid balance reactions but also setting the central nervous system in advance to optimize balance recovery reactions even when a future threat to stability is unexpected. In this review the growing body of evidence that now firmly supports a cortical role in the postural responses to externally induced perturbations is presented. Moreover, an updated framework is advanced to help understand how cortical contributions may influence our resistance to falls and on what timescale. The implications for future studies into the neural control of balance are discussed.

Fractionated Radiation Exposure of Rat Spinal Cords Leads to Latent Neuro- Inflammation in Brain, Cognitive Deficits,and Alterations in Apurinic Endonuclease 1

Ionizing radiation causes degeneration of myelin, the insulating sheaths of neuronal axons, leading to neurological impairment. As radiation research on the central nervous system has predominantly focused on neurons, with few studies addressing the role of glial cells, we have focused our present research on identifying the latent effects of single/ fractionated -low dose of low/ high energy radiation on the role of base excision repair protein Apurinic Endonuclease-1, in the rat spinal cords oligodendrocyte progenitor cells’ differentiation. Apurinic endonuclease-1 is predominantly upregulated in response to oxidative stress by low- energy radiation, and previous studies show significant induction of Apurinic Endonuclease-1 in neurons and astrocytes. Our studies show for the first time, that fractionation of protons cause latent damage to spinal cord architecture while fractionation of HZE (28Si) induce increase in APE1 with single dose, which then decreased with fractionation. The oligodendrocyte progenitor cells differentiation was skewed with increase in immature oligodendrocytes and astrocytes, which likely cause the observed decrease in white matter, increased neuro-inflammation, together leading to the observed significant cognitive defects.