We have employed immunohistochemistry for multiple markers to investigate the structure and possible function of the different compartments of human cerebral wall from the formation of cortical plate at 8 postconceptional weeks (PCW) to the arrival of thalamocortical afferents at 17 PCW. New observations include the subplate emerging as a discrete differentiated layer by 10 PCW, characterized by synaptophysin and vesicular gamma-aminobutyric acid transporter expression also seen in the marginal zone, suggesting that these compartments may maintain a spontaneously active synaptic network even before the arrival of thalamocortical afferents. The subplate expanded from 13 to 17 PCW, becoming the largest compartment and differentiated further, with NPY neurons located in the outer subplate and KCC2 neurons in the inner subplate. Glutamate decarboxylase and calretinin-positive inhibitory neurons migrated tangentially and radially from 11.5 PCW, appearing in larger numbers toward the rostral pole. The proliferative zones, marked by Ki67 expression, developed a complicated structure by 12.5 PCW reflected in transcription factor expression patterns, including TBR2 confined to the inner subventricular and outer ventricular zones and TBR1 weakly expressed in the subventricular zone (SVZ). PAX6 was extensively expressed in the proliferative zones such that the human outer SVZ contained a large reservoir of PAX6-positive potential progenitor cells.

Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value = 7.1 × 10 −6 ), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch's membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels (P-value = 2.2 × 10 −56 ), independently of the AMD-protective CFHR1-3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD.

No abstract

Steroids that activate glucocorticoid receptors (GRs) and mineralocorticoid receptors have important regulatory effects on neural development, plasticity, and the body's stress response. Here, we investigated the role of corticosteroids in regulating the expression of the glial glutamate transporters glial glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter (GLAST) in rat primary astrocytes. The synthetic glucocorticoid dexamethasone provoked a marked increase of GLT-1 transcription and protein levels in cortical astrocytes, whereas GLAST expression remained unaffected. Up-regulation of GLT-1 expression was accompanied by an enhanced glutamate uptake, which could be blocked by the specific GLT-1 inhibitor dihydrokainate. The promoting effect of dexamethasone on GLT-1 gene expression and function was abolished by the GR antagonist mifepristone. A predominant role of the GR was further supported by the observation that corticosterone could elevate GLT-1 expression in a dose-dependent manner, whereas aldosterone, the physiological ligand of the mineralocorticoid receptor, exerted only weak effects even when applied at high concentrations. Moreover, we monitored brain region-specific differences, since all corticosteroids used in this study failed to alter the expression of GLT-1 in midbrain and cerebellar glia, although expression levels of both corticosteroid receptor subtypes were similar in all brain regions analyzed. Dexamethasone, however, modestly enhanced GLT-1 expression in cerebellar glia in combination with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine, suggesting that suppression of GLT-1 expression in cerebellar cultures may at least in part be epigenetically mediated by a DNA methylation-dependent process. Taken together, our data highlight a potential role for glucocorticoids in regulating GLT-1 gene expression during central nervous system development or pathophysiogical processes including stress. Steroid hormones possessing glucocorticoid (GC)2 or mineralocorticoid (MC) activity exert profound regulatory effects in the central nervous system (1). Being synthesized in the adrenal gland and ultimately secreted into circulation, they penetrate the blood brain barrier and influence neuronal development and plasticity. Moreover, GCs are the main effectors of the hypothalamic-pituitary-adrenal axis and regulate the body's stress response by inducing a variety of physiological changes including mobilization of energy from storage sites and the suppression of parts of the immune system (2). Due to their anti-inflammatory properties, they are administered in the treatment of central nervous system diseases such as edema arising from brain tumors, viral encephalitis, bacterial meningitis, and multiple sclerosis (3).The effects of adrenal steroid hormones (GCs and MCs) are classically mediated through the activation of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) (4, 5), which display a wide distribution in the brain. Corticosterone, cortisol, and aldosteron...

Energy metabolism is altered in amyotrophic lateral sclerosis and its animal models. Using metabolic profiling, Allen et al. reveal a loss of metabolic flexibility in induced astrocytes derived from patients with C9orf72 ALS, caused by defects in glycogen, fructose and mitochondrial energy substrate transport.