Lactadherin is a secreted extracellular matrix protein expressed in phagocytes and contributes to the removal of apoptotic cells. We examined lactadherin expression in brain sections of patients with or without Alzheimer's disease and studied its role in the phagocytosis of amyloid -peptide (A). Cells involved in Alzheimer's disease, including vascular smooth muscle cells, astrocytes, and microglia, showed a time-related increase in lactadherin production in culture. Quantitative analysis of the level of lactadherin showed a 35% reduction in lactadherin mRNA expression in the brains of patients with Alzheimer's disease (n ؍ 52) compared with age-matched controls (n ؍ 58; P ؍ 0.003). Interestingly, lactadherin protein was detected in the brains of patients with Alzheimer's disease and controls, with low expression in areas rich in senile plaques and marked expression in areas without A deposition. Using surface plasmon resonance, we observed a direct pro-
Astrocytes and one of their products, IL-6, not only support neurons but also mediate inflammation in the brain. Retinoidrelated orphan receptor-␣ (ROR␣) transcription factor has related roles, being neuro-protective and, in peripheral tissues, antiinflammatory. We examined the relation of ROR␣ to astrocytes and IL-6 using normal and ROR␣ loss-of-function mutant mice. We have shown ROR␣ expression in astrocytes and its up-regulation by pro-inflammatory cytokines. We have also demonstrated that ROR␣ directly trans-activates the Il-6 gene. We suggest that this direct control is necessary to maintain IL-6 basal level in the brain and may be a link between the neuro-supportive roles of ROR␣, IL-6, and astrocytes. Furthermore, after inflammatory stimulation, the absence of ROR␣ results in excessive IL-6 up-regulation, indicating that ROR␣ exerts an indirect repression probably via the inhibition of the NF-B signaling. Thus, our findings indicate that ROR␣ is a pluripotent molecular player in constitutive and adaptive astrocyte physiology.inflammation ͉ staggerer ͉ microglia
The development of the mammalian cerebral cortex involves a series of mechanisms: from patterning, progenitor cell proliferation and differentiation, to neuronal migration. Many factors influence the development of the cerebral cortex to its normal size and neuronal composition. Of these, the mechanisms that influence the proliferation and differentiation of neural progenitor cells are of particular interest, as they may have the greatest consequence on brain size, not only during development but also in evolution. In this context, causative genes of human autosomal recessive primary microcephaly, such as ASPM and MCPH1, are attractive candidates, as many of them show positive selection during primate evolution. MCPH1 causes microcephaly in mice and humans and is involved in a diverse array of molecular functions beyond brain development, including DNA repair and chromosome condensation. Positive selection of MCPH1 in the primate lineage has led to much insight and discussion of its role in brain size evolution. In this review, we will present an overview of MCPH1 from these multiple angles, and whilst its specific role in brain size regulation during development and evolution remain elusive, the pieces of the puzzle will be discussed with the aim of putting together the full picture of this fascinating gene.
Fifteen million babies are born preterm every year and a significant number suffer from permanent neurological injuries linked to white matter injury (WMI). A chief cause of preterm birth itself and predictor of the severity of WMI is exposure to maternal-fetal infection-inflammation such as chorioamnionitis. There are no neurotherapeutics for this WMI. To affect this healthcare need, the repurposing of drugs with efficacy in other white matter injury models is an attractive strategy. As such, we tested the efficacy of GSK247246, an H3R antagonist/inverse agonist, in a model of inflammation-mediated WMI of the preterm born infant recapitulating the main clinical hallmarks of human brain injury, which are oligodendrocyte maturation arrest, microglial reactivity, and hypomyelination. WMI is induced by mimicking the effects of maternal-fetal infection-inflammation and setting up neuroinflammation. We induce this process at the time in the mouse when brain development is equivalent to the human third trimester; postnatal day (P)1 through to P5 with i.p. interleukin-1β (IL-1β) injections. We initiated GSK247246 treatment (i.p at 7 mg/kg or 20 mg/kg) after neuroinflammation was well established (on P6) and it was administered twice daily through to P10. Outcomes were assessed at P10 and P30 with gene and protein analysis. A low dose of GSK247246 (7 mg/kg) lead to a recovery in protein expression of markers of myelin (density of Myelin Basic Protein, MBP & Proteolipid Proteins, PLP) and a reduction in macro- and microgliosis (density of ionising adaptor protein, IBA1 & glial fibrillary acid protein, GFAP). Our results confirm the neurotherapeutic efficacy of targeting the H3R for WMI seen in a cuprizone model of multiple sclerosis and a recently reported clinical trial in relapsing-remitting multiple sclerosis patients. Further work is needed to develop a slow release strategy for this agent and test its efficacy in large animal models of preterm infant WMI.
There is increasing evidence to suggest that the neuronal response to hypoxia is regulated through their interactions with astrocytes. However, the hypoxia-induced molecular mechanisms within astrocytes which influence neuronal death have yet to be characterized. In this study, we investigated the roles of the nuclear receptor ROR␣ (retinoid-related orphan receptor-␣) respectively in neurons and astrocytes during hypoxia using cultures and cocultures of neurons and astrocytes obtained from ROR␣-deficient mice. We found that loss of ROR␣ function in neuronal cultures increases neuronal death after hypoxia, suggesting a cell-autonomous neuroprotective effect of ROR␣. Moreover, wild-type neurons cocultured with ROR␣-deficient astrocytes are characterized by a higher death rate after hypoxia than neurons cocultured with wild-type astrocytes, suggesting that ROR␣ also has a non-cell-autonomous action. By using cocultures of neurons and astrocytes of different genotypes, we showed that this neuroprotective effect of ROR␣ in astrocytes is additive to its effect in neurons, and is mediated in part by cell-to-cell interactions between neurons and astrocytes. We also found that ROR␣ is upregulated by hypoxia in both neurons and astrocytes. Furthermore, our data showed that ROR␣ does not alter oxidative mechanisms during hypoxia but regulates hypoxic inducible factor 1␣ (HIF-1␣) expression, a major regulator of hypoxia sensing, in a cell-specific manner. Indeed, the neuroprotective function of ROR␣ in astrocytes correlates with a downregulation of HIF-1␣ selectively in these cells. Altogether, our results show that ROR␣ is a key molecular player in hypoxia, protecting neurons through its dual action in neurons and astrocytes.
Studies of staggerer mice, in which retinoid-related orphan receptor-alpha (RORα) is mutated, have provided new insights into the critical functions of RORα in various physiological processes in peripheral tissues and in the brain. Staggerer mice present an ataxic phenotype caused by a massive neurodegeneration in the cerebellum. As a result, most of studies have focused on the role of RORα in the development of the cerebellum. Recent studies have expanded the role of RORα to other structures and functions in the brain. RORα was considered to be exclusively expressed in neurons in the brain. Recently, it has been shown that, in addition to its neuronal expression, RORα is expressed in glial cells and particularly in astrocytes in different brain regions. Moreover, RORα has been implicated in the regulation of some astrocyte functions such as the inflammatory function. Several reports have also presented evidence for a role of RORα in diverse pathological processes including oxidative stress-induced apoptosis and cerebral hypoxia. This review therefore focuses on the emerging roles of RORα in the brain and particularly in astrocytes.
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