Induction of the neuronal major histocompatibility complex class I and paired immunoglobulin-like receptor B pathway in the hippocampus with aging and cognitive decline
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE29511 | GEO | 2011/10/30
SECONDARY ACCESSION(S): PRJNA141461
REPOSITORIES: GEO
Similar Datasets
Project description:The aim of this study was to identify alterations in hippocampal synaptic mRNA expression with aging and cognitive decline. Transcriptional profiling and subsequent bioinformatic analysis was performed to identify the most highly regulated pathways of genes. Interestingly, the antigen processing and presentation pathway was identified as the most highly regulated pathway with aging. Adult (12 month) and aged (28 month) Fischer 344 x Brown Norway (F1) hybrid rats were assessed for cognitive performance using the Morris water maze task and were divided into Adult (n=5), Aged Cognitively Intact (n=8), and Aged Cognitively Impaired (n=7) groups. One week following testing, all animals were sacrificed, the hippocampi were dissected, and synaptosomes were isolated for subsequent transcriptomic profiling. Only 5 cognitively intact animals were processed on the arrays.
2011-10-29 | E-GEOD-29511 | biostudies-arrayexpress
Project description:amphibian MHC IIB1 Raw sequence reads
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Project description:In placental mammals, natural killer (NK) cells are a population of lymphocytes that make unique contributions to immune defence and reproduction, functions essential for survival of individuals, populations and species. Modulating these functions are conserved and variable NK-cell receptors that recognize epitopes of major histocompatibility complex (MHC) class I molecules. In humans, for example, recognition of human leucocyte antigen (HLA)-E by the CD94:NKG2A receptor is conserved, whereas recognition of HLA-A, B and C by the killer cell immunoglobulin-like receptors (KIRs) is diversified. Competing demands of the immune and reproductive systems, and of T-cell and NK-cell immunity-combined with the segregation on different chromosomes of variable NK-cell receptors and their MHC class I ligands-drive an unusually rapid evolution that has resulted in unprecedented levels of species specificity, as first appreciated from comparison of mice and humans. Counterparts to human KIR are present only in simian primates. Observed in these species is the coevolution of KIR and the four MHC class I epitopes to which human KIR recognition is restricted. Unique to hominids is the emergence of the MHC-C locus as a supplier of specialized and superior ligands for KIR. This evolutionary trend is most highly elaborated in the chimpanzee. Unique to the human KIR locus are two groups of KIR haplotypes that are present in all human populations and subject to balancing selection. Group A KIR haplotypes resemble chimpanzee KIR haplotypes and are enriched for genes encoding KIR that bind HLA class I, whereas group B KIR haplotypes are enriched for genes encoding receptors with diminished capacity to bind HLA class I. Correlating with their balance in human populations, B haplotypes favour reproductive success, whereas A haplotypes favour successful immune defence. Evolution of the B KIR haplotypes is thus unique to the human species.
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Project description:Recent microarray studies in the hippocampus of rodents or Alzheimerâs disease (AD) subjects have identified a substantial number of cellular pathways/processes correlated with aging and cognitive decline. However, the temporal relationships among these expression changes or with cognitive impairment have not been studied in depth. Here, using Affymetrix microarrays, immunohistochemistry and Morris water maze cognitive testing across 5 age groups of male F344 rats (n=9-15/group, one microarray per animal), we systematically analyzed the temporal sequence and cellular localization of aging changes in expression. These were correlated with performance scores on the hippocampus-dependent Morris Water Maze task. Significant microarray results were sorted in to Early, Intermediate, Midlife, and Late patterns of expression, and functionally categorized (Early- downregulated neural development, lipid synthesis and energy-utilization; upregulated ribosomal synthesis, growth, stress/inflammatory, lysosome and protein/lipid degradation. Intermediate- increased defense/inflammatory activation and decreased transporter activity; Midlife- downregulated energy-dependent signaling and neurite growth, upregulated astroglial activation, Ca2+-binding, cholesterol/lipid trafficking, myelinogenic processes and additional lysosome/inflammation; Late- further recruitment of genes in already-altered pathways). Immunohistochemistry revealed a primarily astrocytic localization of the processes upregulated in midlife, as well as increased density of myelin proteins. Evidence of cognitive impairment first appeared in the 12-month-old group (midlife) and was increased further in the 23-month-old group, exhibiting the highest correlations with some upregulated genes related to cholesterol transport (e.g., Apoe, Abca2), protein management and ion binding. Some upregulated genes for inflammation (Il6st) and myelinogenesis (Pmp22) also correlated with impairment. Together, the data are consistent with a novel sequential cascade model of brain aging in which metabolic alterations early in maturity are followed by inflammation and midlife activation of an astrocyte-centered cholesterol trafficking pathway that stimulates oligodendrocyte remyelination programs. Importantly, this cholesterol trafficking pathway also may compete for astroglial bioenergetic support of neurons, in turn, leading to downregulation of energy-dependent pathways needed to sustain cognitive functions. Experiment Overall Design: Fisher 344 rats aged 3 (n = 9), 6 (n = 9), 9 (n = 9), 12 (n = 9), or 25 (n = 15; but see below) months were behaviorally characterized on the Morris water maze. Briefly, animals were placed in a circular water bath chamber with a partially submerged platform. Three times per day for three days, animals were placed at randomized starting points with the goal of locating the hidden platform. Generally, animals became better at locating the platform, and by the third day of training, were reliably swimming directly to the platform despite randomized starting loci. On the fourth day, the platform was removed and the degree to which the animals focused their searches on the area that previously contained the platform was measured. On the last day of behavior, animals were given a cue trial in which the platform was raised above the water level so that the rats could see it. Measures taken from the behavior study included path length (how long did the animal swim prior to locating the platform/ platform area), latency to platform in seconds, and velocity (centimeters/ second; swim speed). Two aged animals (E2 and E12) were removed from the study for poor health, reducing the 23 month cohort (n = 13). Twelve to twenty four hours after the last behavioral session, animals were killed and their hippocampi removed. The right hippocampus went to immunohistochemistry for quantification and localization of selected protein products. The left hippocampus was dissected, the CA1 region removed and frozen in dry ice prior to microarray processing. mRNA was extracted from each animal's tissue by standard Affymetrix protocols (see Blalock et al., 2003) and hybridized to individual microarrays (RAE 230A; N = 49 arrays in total). Results were processed with the MAS5 algorithm and subjected to âall probe setâ scaling with a target intensity of 500. Probe sets were filtered for presence (> = 5 presence calls study wide) and gene symbol level annotation prior to statistical analysis. 1-ANOVA across age was used to identify aging-related probe sets/genes (p <= 0.05). Aging-related genes were subjected to post hoc template correlation to determine the pattern of age-related change, and further, within the 12 and 23 month old groups, Pearson's correlation with behavioral scores was used to identify genes whose expression levels correlated significantly (p <= 0.05) with behavior. Twelve and 23 month old groups were chosen for this correlation analysis as they showed the greatest variability among similarly aged animals, suggesting that these ages show important cognitive transition phases during aging-related cognitive decline. Functional grouping analysis was performed using the DAVID suite of on-line tools.
2009-01-25 | E-GEOD-9990 | biostudies-arrayexpress
Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1β selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1β. Consistent with our findings in mice, selective hypomethylation of IL-1β at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases. Study of changes related to alterations of SIRT1 levels in microglia of young and aged animals and in models of neurodegenerative dementia
2014-10-01 | E-GEOD-56452 | biostudies-arrayexpress
Project description:Sirenians share with cetaceans and pinnipeds several convergent traits selected for the aquatic lifestyle. Living in water poses new challenges not only for locomotion and feeding but also for combating new pathogens, which may render the immune system one of the best tools aquatic mammals have for dealing with aquatic microbial threats. So far, only cetaceans have had their class II Major Histocompatibility Complex (MHC) organization characterized, despite the importance of MHC genes for adaptive immune responses. This study aims to characterize the organization of the marine mammal class II MHC using publicly available genomes. We located class II sequences in the genomes of one sirenian, four pinnipeds and eight cetaceans using NCBI-BLAST and reannotated the sequences using local BLAST search with exon and intron libraries. Scaffolds containing class II sequences were compared using dotplot analysis and introns were used for phylogenetic analysis. The manatee class II region shares overall synteny with other mammals, however most DR loci were translocated from the canonical location, past the extended class II region. Detailed analysis of the genomes of closely related taxa revealed that this presumed translocation is shared with all other living afrotherians. Other presumptive chromosome rearrangements in Afrotheria are the deletion of DQ loci in Afrosoricida and deletion of DP in E. telfairi. Pinnipeds share the main features of dog MHC: lack of a functional pair of DPA/DPB genes and inverted DRB locus between DQ and DO subregions. All cetaceans share the Cetartiodactyla inversion separating class II genes into two subregions: class IIa, with DR and DQ genes, and class IIb, with non-classic genes and a DRB pseudogene. These results point to three distinct and unheralded class II MHC structures in marine mammals: one canonical organization but lacking DP genes in pinnipeds; one bearing an inversion separating IIa and IIb subregions lacking DP genes found in cetaceans; and one with a translocation separating the most diverse class II gene from the MHC found in afrotherians and presumptive functional DR, DQ, and DP genes. Future functional research will reveal how these aquatic mammals cope with pathogen pressures with these divergent MHC organizations.
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Project description:Recent microarray studies in the hippocampus of rodents or Alzheimer’s disease (AD) subjects have identified a substantial number of cellular pathways/processes correlated with aging and cognitive decline. However, the temporal relationships among these expression changes or with cognitive impairment have not been studied in depth. Here, using Affymetrix microarrays, immunohistochemistry and Morris water maze cognitive testing across 5 age groups of male F344 rats (n=9-15/group, one microarray per animal), we systematically analyzed the temporal sequence and cellular localization of aging changes in expression. These were correlated with performance scores on the hippocampus-dependent Morris Water Maze task. Significant microarray results were sorted in to Early, Intermediate, Midlife, and Late patterns of expression, and functionally categorized (Early- downregulated neural development, lipid synthesis and energy-utilization; upregulated ribosomal synthesis, growth, stress/inflammatory, lysosome and protein/lipid degradation. Intermediate- increased defense/inflammatory activation and decreased transporter activity; Midlife- downregulated energy-dependent signaling and neurite growth, upregulated astroglial activation, Ca2+-binding, cholesterol/lipid trafficking, myelinogenic processes and additional lysosome/inflammation; Late- further recruitment of genes in already-altered pathways). Immunohistochemistry revealed a primarily astrocytic localization of the processes upregulated in midlife, as well as increased density of myelin proteins. Evidence of cognitive impairment first appeared in the 12-month-old group (midlife) and was increased further in the 23-month-old group, exhibiting the highest correlations with some upregulated genes related to cholesterol transport (e.g., Apoe, Abca2), protein management and ion binding. Some upregulated genes for inflammation (Il6st) and myelinogenesis (Pmp22) also correlated with impairment. Together, the data are consistent with a novel sequential cascade model of brain aging in which metabolic alterations early in maturity are followed by inflammation and midlife activation of an astrocyte-centered cholesterol trafficking pathway that stimulates oligodendrocyte remyelination programs. Importantly, this cholesterol trafficking pathway also may compete for astroglial bioenergetic support of neurons, in turn, leading to downregulation of energy-dependent pathways needed to sustain cognitive functions. Keywords: aging time course
2009-01-18 | GSE9990 | GEO
Project description:Major histocompatibility complex (MHC) class I and class II molecules bind to and display peptidic antigens acquired from pathogens that are recognized by lymphocytes coordinating and executing adaptive immune responses. The two classes of MHC proteins have nearly identical tertiary structures and were derived from a common ancestor that probably existed not long before the emergence of the cartilaginous fish. Class I and class II genes are genetically linked in tetrapods but are not syntenic in teleost fish, a phylogenetic taxon derived from the oldest vertebrate ancestor examined to date. Cartilaginous fish (sharks, skates, and rays) are in the oldest taxon of extant jawed vertebrates; we have carried out segregation analyses in two families of nurse sharks and one family of the banded houndshark that revealed a close linkage of class IIalpha and beta genes both with each other and with the classical class I (class Ia) gene. These results strongly suggest that the primordial duplication giving rise to classical class I and class II occurred in cis, and the close linkage between these two classes of genes has been maintained for at least 460 million years in representatives of most vertebrate taxa.
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Project description:Chronic inflammation in atherosclerosis is responsible for plaque instability through alterations in extracellular matrix. Previously, we demonstrated that major histocompatibility class II (MHC II) transactivator (CIITA) in a complex with regulatory factor for X box 5 (RFX5) is a crucial protein mediating interferon (IFN)-gamma-induced repression of collagen type I gene transcription in fibroblasts. This article demonstrates that, in smooth muscle cells (SMCs), IFN-gamma dramatically increases the expression of CIITA isoforms III and IV, with no increase in expression of CIITA isoform I. Expression of CIITA III and IV correlates with decreased collagen type I and increased MHC II gene expression. Exogenous expression of CIITA I, III, and IV, in transiently transfected SMCs, represses collagen type I promoters (COL1A1 and COL1A2) and activates MHC II promoter. Levels of CIITA and RFX5 increase in the nucleus of cells treated with IFN-gamma. Moreover, simvastatin lowers the IFN-gamma-induced expression of RFX5 and MHC II in addition to repressing collagen expression. However, simvastatin does not block the IFN-gamma-induced expression of CIITA III and IV, suggesting a CIITA-independent mechanism. This first demonstration that RFX5 and CIITA isoforms are expressed in SMCs after IFN-gamma stimulation suggest that CIITA could be a key factor in plaque stability in atherosclerosis.
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Project description:Extracellular vesicles (EVs) are released by most cell types and have been associated with multiple immunomodulatory functions. MHC class I molecules have crucial roles in antigen presentation and in eliciting immune responses and are known to be incorporated into EVs. However, the MHC class I immunopeptidome of EVs has not been established. Here, using a small-scale immunoisolation of the antigen serotypes HLA-A*02:01 and HLA-B*27:05 expressed on the Epstein-Barr virus-transformed B cell line Jesthom and MS of the eluted peptides from both cells and EVs, we identified 516 peptides that bind either HLA-A*02:01 or HLA-B*27:05. Of importance, the predicted serotype-binding affinities and peptide-anchor motifs did not significantly differ between the peptide pools isolated from cells or EVs, indicating that during EV biogenesis, no obvious editing of the MHC class I immunopeptidome occurs. These results, for the first time, establish EVs as a source of MHC class I peptides that can be used for the study of the immunopeptidome and in the discovery of potential neoantigens for immunotherapies.
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