Amyloid-beta peptide (Abeta) interacts with the vasculature to influence Abeta levels in the brain and cerebral blood flow, providing a means of amplifying the Abeta-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Abeta infusion and studies in genetically manipulated mice show that Abeta interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Abeta across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Abeta-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Abeta in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Abeta-vascular interactions, including development of cerebral amyloidosis.
Neurovascular dysfunction substantially contributes to Alzheimer disease. Here, we show that transcriptional profiling of human brain endothelial cells (BECs) defines a subset of genes whose expression is age-independent but is considerably altered in Alzheimer disease, including the homeobox gene MEOX2 (also known as GAX), a regulator of vascular differentiation, whose expression is low in Alzheimer disease. By using viral-mediated MEOX2 gene silencing and transfer, we show that restoring expression of the protein it encodes, GAX, in BECs from individuals with Alzheimer disease stimulates angiogenesis, transcriptionally suppresses AFX1 forkhead transcription factor-mediated apoptosis and increases the levels of a major amyloid-beta peptide (Abeta) clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP), at the blood-brain barrier. In mice, deletion of Meox2 (also known as Gax) results in reductions in brain capillary density and resting cerebral blood flow, loss of the angiogenic response to hypoxia in the brain and an impaired Abeta efflux from brain caused by reduced LRP levels. The link of MEOX2 to neurovascular dysfunction in Alzheimer disease provides new mechanistic and therapeutic insights into this illness.
Background: Recent conceptual models argue that early life adversity (ELA) accelerates development, which may contribute to poor mental and physical health outcomes. Evidence for accelerated development in youth comes from studies of telomere shortening or advanced pubertal development following circumscribed ELA experiences and neuroimaging studies of circuits involved in emotional processing. It remains unclear whether all ELA is associated with accelerated development across global metrics of biological aging or whether this pattern emerges following specific adversity types. Methods: In 247 children and adolescents aged 8-16 years with wide variability in ELA exposure, we evaluated the hypothesis that early environments characterized by threat, but not deprivation, would be associated with accelerated development across two global biological aging metrics: DNA methylation (DNAm) age and pubertal stage relative to chronological age. We also examined whether accelerated development explained associations of ELA with depressive symptoms and externalizing problems. Results: Exposure to threat-related ELA (e.g., violence) was associated with accelerated DNAm age and advanced pubertal stage, but exposure to deprivation (e.g., neglect, food insecurity) was not. In models including both ELA types, threat-related ELA was uniquely associated with accelerated DNAm age (ß=0.18) and advanced pubertal stage (ß=0.28), whereas deprivation was
Results suggest that traumatic stress is associated with advanced epigenetic age and raise the possibility that cells integral to immune system maintenance and responsivity play a role in this. This study highlights the need for additional research into the biological mechanisms linking traumatic stress to accelerated DNA methylation age and the importance of furthering our understanding of the neurobiological and health consequences of PTSD.
A combined forward and reverse genetic approach was undertaken to test the candidacy of IRAK1 (interleukin-1 receptor associated kinase-1) as an X chromosome-encoded risk factor for systemic lupus erythematosus (SLE). In studying Ϸ5,000 subjects and healthy controls, 5 SNPs spanning the IRAK1 gene showed disease association (P values reaching 10 ؊10 , odds ratio >1.5) in both adult-and childhoodonset SLE, in 4 different ethnic groups, with a 4 SNP haplotype (GGGG) being strongly associated with the disease. The functional role of IRAK1 was next examined by using congenic mouse models bearing the disease loci: Sle1 or Sle3. IRAK1 deficiency abrogated all lupusassociated phenotypes, including IgM and IgG autoantibodies, lymphocytic activation, and renal disease in both models. In addition, the absence of IRAK1 reversed the dendritic cell ''hyperactivity'' associated with Sle3. Collectively, the forward genetic studies in human SLE and the mechanistic studies in mouse models establish IRAK1 as a disease gene in lupus, capable of modulating at least 2 key checkpoints in disease development. This demonstration of an X chromosome gene as a disease susceptibility factor in human SLE raises the possibility that the gender difference in SLE may in part be attributed to sex chromosome genes.autoimmune disease ͉ genetic association ͉ SNP ͉ inflammation ͉ interferon
Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/ mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function.F ine localization of the polymorphisms responsible for genotype-phenotype correlations is emerging as a difficult hurdle in the implementation and interpretation of genetic association studies. Candidate gene studies and, more recently, genome-wide association studies (GWAS), have begun to elucidate the complex genetic profile of systemic lupus erythematosus (SLE) with identification of ∼30 risk loci (1-3). However, for almost all these identified loci, the causal polymorphism that leads to lupus susceptibility has not been discovered. GWAS have been praised for representing an "agnostic" approach that is unbiased by prior assumptions regarding genetic association with the disease. However, such an approach typically ignores all valuable prior information collected over decades about the pathogenesis and genetic basis of diseases that have been previously studied. This inevitably leads to the inclusion of regions (and additional SNPs) that have little to no possibility of being associated with a disease, increasing the number of tests. More tests mean a more stringent multiple testing correction and a reduction of power or a greater number of subjects to overcome the reduction of power. To avoid this reduction of power, we have developed a two-step bioinformatics-driven design that increases the power of gene association studies using a partial Bayesian approach. The...
In a Genome Wide Association Study (GWAS) of individuals of European ancestry afflicted with Systemic Lupus Erythematosus (SLE) the extensive utilization of imputation, stepwise multiple regression, lasso regularization, and increasing study power by utilizing False Discovery Rate (FDR) instead of a Bonferroni multiple test correction enabled us to identify 13 novel non-human leukocyte antigen (HLA) genes and confirmed the association of 4 genes previously reported to be associated. Novel genes associated with SLE susceptibility included two transcription factors (EHF, and MED1), two components of the NFκB pathway (RASSF2 and RNF114), one gene involved in adhesion and endothelial migration (CNTN6), and two genes involved in antigen presentation (BIN1 and SEC61G). In addition, the strongly significant association of multiple single nucleotide polymorphisms (SNPs) in the HLA region was assigned to HLA alleles and serotypes and deconvoluted into four primary signals. The novel SLE-associated genes point to new directions for both the diagnosis and treatment of this debilitating autoimmune disease.
Although archaea have a similar cellular organization as other prokaryotes, the lipid composition of their membranes and their cell surface is unique. Here we discuss recent developments in our understanding of the archaeal protein secretion mechanisms, the assembly of macromolecular cell surface structures, and the release of S-layer-coated vesicles from the archaeal membrane. The Archaeal Cell EnvelopeThe ability of many archaea to endure extreme conditions in hostile environments intrigues researchers to study the molecular mechanisms and specific adaptations involved. Very early, it was realized that the structure of the archaeal cell envelope differs substantially from that of bacteria [1]. With the only exception of Ignicoccus which exhibits an outer membrane enclosing a huge periplasmic space [2], known archaea possess only a single membrane. This cytoplasmic membrane is enclosed by an S-layer, a two-dimensional protein crystal that fully covers the cells (see review Jarrell et al. in this issue). In contrast to bacterial ester lipids, archaeal lipids consist of repeating isoprenyl groups linked to a glycerol backbone through an ether linkage [3,4]. These lipids typically form diether bilayer membranes similar to membranes of eukarya and bacteria. Hyperthermoacidophiles contain tetraether lipids that consist of C 40 isoprenoid acyl chains that span the membrane entirely forming a monolayer membrane [5]. These membranes are extremely proton impermeable and enable these organisms to survive under conditions that the extracellular pH is up to 4 units below that of the cytoplasm [6]. Another peculiarity is that most of the extracellular proteins of archaea are glycosylated via N-and O-glycosylation. Finally, Archaea do not produce any murein, and only some methanogenic species are known to produce pseudomurein [7].As the archaeal cell surface is so different from that of bacteria and eukarya, unique mechanisms must exist to form and shape it. Until recently most of our knowledge of protein secretion and on the assembly of the cell surface components in archaea was obtained by comparative genomic studies. However, in recent years tremendous progress has been made in our understanding of the assembly and function of cell surface structures and both the structural and functional basis of protein translocation across the archaeal membrane. Here we will discuss these topics with an emphasis on the cell surface structures. Protein Secretion Transport of Unfolded Proteins Across the CytoplasmicMembrane. The ability to transport proteins across membranes is vital for cell viability. In general, the systems found in archaea that mediate protein transport across the cytoplasmic membrane are similar to those of bacteria. In archaea most proteins are secreted across the cytoplasmic membrane by the general secretion (Sec) or Twin arginine translocase (Tat) route (see Figure 1). The Sec pathway consists of a universally conserved translocation complex embedded in the membrane, which is termed SecYEG in bacteria and Sec61p ...
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