C9
Complement component C9 precursor [Contains: Complement component C9a; Complement component C9b]
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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation . Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells . Here we show in mice that loss of C9orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of C9orf72. Dendritic cells isolated from C9orf72 mice show marked early activation of the type I interferon response, and C9orf72 myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein-a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in C9orf72 myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in C9orf72 immune cells as well as splenomegaly and inflammation in C9orf72 mice. Moreover, mice lacking one or both copies of C9orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING.
MeSH Terms
- Aging
- Amyotrophic Lateral Sclerosis
- Animals
- C9orf72 Protein
- Dendritic Cells
- Encephalomyelitis, Autoimmune, Experimental
- Female
- Humans
- Inflammation
- Interferon Type I
- Membrane Proteins
- Mice
- Myeloid Cells
- Neoplasms
- T-Lymphocytes
Hexanucleotide repeat expansions of variable size in C9orf72 are the most prevalent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense transcripts of the expansions are translated by repeat-associated non-AUG translation into five dipeptide repeat proteins (DPRs). Of these, the polyGR, polyPR and, to a lesser extent, polyGA DPRs are neurotoxic, with polyGA the most abundantly detected DPR in patient tissue. Trans-cellular transmission of protein aggregates has recently emerged as a major driver of toxicity in various neurodegenerative diseases. In vitro evidence suggests that the C9 DPRs can spread. However, whether this phenomenon occurs under more complex in vivo conditions remains unexplored. Here, we used the adult fly brain to investigate whether the C9 DPRs can spread in vivo upon expression in a subset of neurons. We found that only polyGA can progressively spread throughout the brain, which accumulates in the shape of aggregate-like puncta inside recipient cells. Interestingly, GA transmission occurred as early as 3 days after expression induction. By comparing the spread of 36, 100 and 200 polyGA repeats, we found that polyGA spread is enhanced upon expression of longer GA DPRs. Transmission of polyGA is greater in older flies, indicating that age-associated factors exacerbate the spread. These data highlight a unique propensity of polyGA to spread throughout the brain, which could contribute to the greater abundance of polyGA in patient tissue. In addition, we present a model of early GA transmission that is suitable for genetic screens to identify mechanisms of spread and its consequences in vivo.
MeSH Terms
- Aging
- Alanine
- Animals
- Animals, Genetically Modified
- Brain
- C9orf72 Protein
- DNA Repeat Expansion
- Dipeptides
- Drosophila
- Female
- Glycine
Keywords
- Ageing
- C9orf72
- Dipeptide repeat proteins
- Drosophila
- PolyGA
- Repeat size
- Spread
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons (MNs). It was shown that human astrocytes with mutations in genes associated with ALS, like C9orf72 (C9) or SOD1, reduce survival of MNs. Astrocyte toxicity may be related to their dysfunction or the release of neurotoxic factors. We used human induced pluripotent stem cell-derived astrocytes from ALS patients carrying C9orf72 mutations and non-affected donors. We utilized these cells to investigate astrocytic induced neuronal toxicity, changes in astrocyte transcription profile as well as changes in secretome profiles. We report that C9-mutated astrocytes are toxic to MNs via soluble factors. The toxic effects of astrocytes are positively correlated with the length of astrocyte propagation in culture, consistent with the age-related nature of ALS. We show that C9-mutated astrocytes downregulate the secretion of several antioxidant proteins. In line with these findings, we show increased astrocytic oxidative stress and senescence. Importantly, media conditioned by C9-astrocytes increased oxidative stress in wild type MNs. Our results suggest that dysfunction of C9-astrocytes leads to oxidative stress of themselves and MNs, which probably contributes to neurodegeneration. Our findings suggest that therapeutic strategies in familial ALS must not only target MNs but also focus on astrocytes to abrogate nervous system injury.
MeSH Terms
- Amyotrophic Lateral Sclerosis
- Animals
- Astrocytes
- Biomarkers
- C9orf72 Protein
- Cells, Cultured
- Cellular Reprogramming
- Cellular Senescence
- Cerebral Cortex
- Disease Models, Animal
- Gene Expression Profiling
- Glutamic Acid
- Humans
- Induced Pluripotent Stem Cells
- Mice
- Motor Neurons
- Mutation
- Oxidative Stress
- Proteomics
- Reactive Oxygen Species
Keywords
- Amyotrophic lateral sclerosis
- Astrocytes
- Neurotoxicity
- Oxidative stress
- Senescence
- iPSC
The complement system is essential for an adequate immune response. Much attention has been given to the role of complement in disease. However, to better understand complement in pathology, it is crucial to first analyze this system under different physiological conditions. The aim of the present study was therefore to investigate the inter-individual variation in complement activity and the influences of age and sex. Complement levels and functional activity were determined in 120 healthy volunteers, 60 women, 60 men, age range 20-69 year. Serum functional activity of the classical pathway (CP), lectin pathway activated by mannan (MBL-LP) and alternative pathway (AP) was measured in sera, using deposition of C5b-9 as readout. In addition, levels of C1q, MBL, MASP-1, MASP-2, ficolin-2, ficolin-3, C2, C4, C3, C5, C6, C7, C8, C9, factor B, factor D, properdin, C1-inhibitor and C4b-binding protein, were determined. Age- and sex-related differences were evaluated. Significantly lower AP activity was found in females compared to males. Further analysis of the AP revealed lower C3 and properdin levels in females, while factor D concentrations were higher. MBL-LP activity was not influenced by sex, but MBL and ficolin-3 levels were significantly lower in females compared to males. There were no significant differences in CP activity or CP components between females and males, nevertheless females had significantly lower levels of the terminal components. The CP and AP activity was significantly higher in the elderly, in contrast to MBL-LP activity. Moreover, C1-inhibitor, C5, C8, and C9 increased with age in contrast to a decrease of factor D and C3 levels. In-depth analysis of the functional activity assays revealed that MBL-LP activity was predominantly dependent on MBL and MASP-2 concentration, whereas CP activity relied on C2, C1-inhibitor and C5 levels. AP activity was strongly and directly associated with levels of C3, factor B and C5. This study demonstrated significant sex and age-related differences in complement levels and functionality in the healthy population. Therefore, age and sex analysis should be taken into consideration when discussing complement-related pathologies and subsequent complement-targeted therapies.
MeSH Terms
- Adult
- Aged
- Aging
- Complement Activation
- Complement System Proteins
- European Continental Ancestry Group
- Female
- Humans
- Male
- Middle Aged
- Sex Characteristics
Keywords
- complement
- gender
- health
- innate imunity
- sex and age
Individual lifespans vary widely, and longevity is the main concern from ancient to modern times. This study is aimed to identify plasma proteins associated with longevity by proteomics technique. Tandem mass tags (TMT)-based proteomics analysis is performed for the plasma of Bama longevity group and a control group to analyze the differentially expressed proteins (DEPs). A validation set is used to verify the results of TMT-based proteomics. Between Bama natives and the control individuals, the authors identify 175 DEPs, which are mainly involved in complement and coagulation cascades, metabolism of glyco and lipid, and regulation of actin cytoskeleton. Consistent with the proteomic analysis, plasma levels of MMP2, CCL5, and PF4 are significantly lower in Bama participants than in controls, whereas IGFBP2 and C9 increase in Bama individuals, in the validation set. By ROC analysis, combinations of these five proteins result in a high AUC value (0.991, 95% CI, 0.929-1.000, p < 0.0001) to distinguish longevous participants from controls. The results highlight the roles of complement and coagulation cascades, metabolism of glyco and lipid, and inflammatory and immune response may play important roles in longevity. And the DEPs may serve as clinically useful biomarkers for healthy aging and predicting longevity.
MeSH Terms
- Adult
- Aged, 80 and over
- Biomarkers
- Blood Proteins
- Female
- Humans
- Longevity
- Male
- Middle Aged
- Proteomics
- Tandem Mass Spectrometry
Keywords
- TMT
- bama longevity hotspot
- complement and coagulation cascades
- gluconeogenesis/glycolysis
- proteomics
The arginine-rich dipeptide repeats (DPRs) are highly toxic products from the C9orf72 repeat expansion mutations, which are the most common causes of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the effects of DPRs in the synaptic regulation and excitotoxicity remain elusive, and how they contribute to the development of FTD is primarily unknown. By expressing DPRs with different toxicity strength in various neuronal populations in a [i]Drosophila[/i] model, we unexpectedly found that Glycine-Arginine/Proline-Arginine (GR/PR) with 36 repeats could lead to neurodegenerative phenotypes only when they were expressed in glutamatergic neurons, including motor neurons. We detected increased extracellular glutamate and intracellular calcium levels in GR/PR-expressing larval ventral nerve cord and/or adult brain, accompanied by significant increase of synaptic boutons and active zones in larval neuromuscular junctions. Inhibiting the vesicular glutamate transporter expression or blocking the NMDA receptor in presynaptic glutamatergic motor neurons could effectively rescue the motor deficits and shortened life span caused by poly GR/PR, thus indicating a cell-autonomous excitotoxicity mechanism. Therefore, our results have revealed a novel mode of synaptic regulation by arginine-rich C9 DPRs expressed at more physiologically relevant toxicity levels and provided a mechanism that could contribute to the development of C9-related ALS and FTD. C9orf72 dipeptide repeats (DPRs) are key toxic species causing ALS/FTD, but their roles in synaptic regulation and excitotoxicity are unclear. Using C9orf72 DPRs with various toxicity strength, we have found that the arginine-rich DPRs cause selective degeneration in [i]Drosophila[/i] glutamatergic neurons and revealed an NMDA receptor-dependent cell-autonomous excitotoxicity mechanism. Therefore, this study has advanced our understanding of C9orf72 DPR functions in synaptic regulation and excitotoxicity and provided a new mechanism that could contribute to the development of C9-related ALS and FTD.
MeSH Terms
- Animals
- Animals, Genetically Modified
- Arginine
- C9orf72 Protein
- Dipeptides
- Drosophila Proteins
- Drosophila melanogaster
- Genes, Reporter
- Glutamic Acid
- Glycine
- Larva
- Longevity
- Male
- Minisatellite Repeats
- Motor Activity
- Motor Neurons
- Nerve Degeneration
- Neurons
- Proline
- Vesicular Glutamate Transport Proteins
Keywords
- ALS
- C9orf72 dipeptide repeats
- FTD
- cell-autonomous
- excitotoxicity
- selective neurotoxicity
The lack of high-throughput methods to analyze the adipose tissue protein composition limits our understanding of the protein networks responsible for age and diet related metabolic response. We have developed an approach using multiple-dimension liquid chromatography tandem mass spectrometry and extended multiplexing (24 biological samples) with tandem mass tags (TMT) labeling to analyze proteomes of epididymal adipose tissues isolated from mice fed either low or high fat diet for a short or a long-term, and from mice that aged on low [i]versus[/i] high fat diets. The peripheral metabolic health (as measured by body weight, adiposity, plasma fasting glucose, insulin, triglycerides, total cholesterol levels, and glucose and insulin tolerance tests) deteriorated with diet and advancing age, with long-term high fat diet exposure being the worst. In response to short-term high fat diet, 43 proteins representing lipid metabolism ([i]e.g.[/i] AACS, ACOX1, ACLY) and red-ox pathways ([i]e.g.[/i] CPD2, CYP2E, SOD3) were significantly altered (FDR < 10%). Long-term high fat diet significantly altered 55 proteins associated with immune response ([i]e.g.[/i] IGTB2, IFIT3, LGALS1) and rennin angiotensin system ([i]e.g.[/i] ENPEP, CMA1, CPA3, ANPEP). Age-related changes on low fat diet significantly altered only 18 proteins representing mainly urea cycle ([i]e.g.[/i] OTC, ARG1, CPS1), and amino acid biosynthesis ([i]e.g.[/i] GMT, AKR1C6). Surprisingly, high fat diet driven age-related changes culminated with alterations in 155 proteins involving primarily the urea cycle ([i]e.g.[/i] ARG1, CPS1), immune response/complement activation ([i]e.g.[/i] C3, C4b, C8, C9, CFB, CFH, FGA), extracellular remodeling ([i]e.g.[/i] EFEMP1, FBN1, FBN2, LTBP4, FERMT2, ECM1, EMILIN2, ITIH3) and apoptosis ([i]e.g.[/i] YAP1, HIP1, NDRG1, PRKCD, MUL1) pathways. Using our adipose tissue tailored approach we have identified both age-related and high fat diet specific proteomic signatures highlighting a pronounced involvement of arginine metabolism in response to advancing age, and branched chain amino acid metabolism in early response to high fat feeding. Data are available via ProteomeXchange with identifier PXD005953.
MeSH Terms
- Adipose Tissue
- Aging
- Animals
- Diet, High-Fat
- Epididymis
- Gene Regulatory Networks
- Immunoblotting
- Male
- Mass Spectrometry
- Metabolic Networks and Pathways
- Mice, Inbred C57BL
- Proteome
- Proteomics
- Reproducibility of Results
- Sample Size
To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within all reported AMD loci and related pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (odds ratio (OR) = 3.6; P = 2 × 10(-8)). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association with disease. We observed significant association with rare missense alleles in genes other than CFI. Genotyping in 5,115 independent samples confirmed associations with AMD of an allele in C3 encoding p.Lys155Gln (replication P = 3.5 × 10(-5), OR = 2.8; joint P = 5.2 × 10(-9), OR = 3.8) and an allele in C9 encoding p.Pro167Ser (replication P = 2.4 × 10(-5), OR = 2.2; joint P = 6.5 × 10(-7), OR = 2.2). Finally, we show that the allele of C3 encoding Gln155 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder.
MeSH Terms
- Aging
- Amino Acid Substitution
- Base Sequence
- Complement Activation
- Complement C3
- Complement C9
- Complement Factor I
- Genetic Predisposition to Disease
- Genetic Variation
- Genotype
- Humans
- Macular Degeneration
- Risk
- Sequence Analysis, DNA
Intervertebral disc degeneration is considered to be a major feature of low back pain. Furthermore, oxidative stress has been shown to be an important factor in degenerative diseases such as osteoarthritis and is considered a cause of intervertebral disc degeneration. The purpose of this study was to clarify the correlation between oxidative stress and intervertebral disc degeneration using Broad complex-Tramtrack-Bric-a-brac and cap'n'collar homology 1 deficient (Bach 1-/-) mice which highly express heme oxygenase-1 (HO-1). HO-1 protects cells from oxidative stress. Caudal discs of 12-week-old and 1-year-old mice were evaluated as age-related models. Each group and period, 5 mice (a total of 20 mice, a total of 20 discs) were evaluated as age-related model. C9-C10 caudal discs in 12-week-old Bach 1-/- and wild-type mice were punctured using a 29-gauge needle as annulus puncture model. Each group and period, 5 mice (a total of 60 mice, a total of 60 discs) were evaluated. The progress of disc degeneration was evaluated at pre-puncture, 1, 2, 4, 8 and 12 weeks post-puncture. Radiographic, histologic and immunohistologic analysis were performed to compare between Bach 1-/- and wild-type mice. In the age-related model, there were no significant differences between Bach 1-/- and wild-type mice radiologically and histologically. However, in the annulus puncture model, histological scoring revealed significant difference at 8 and 12 weeks post-puncture. The number of HO-1 positive cells was significantly greater in Bach 1-/- mice at every period. The apoptosis rate was significantly lower at 1 and 2 weeks post-puncture in Bach 1-/- mice. Oxidative stress prevention may avoid the degenerative process of the intervertebral disc after puncture, reducing the number of apoptosis cells. High HO-1 expression may also inhibit oxidative stress and delay the process of intervertebral disc degeneration.
MeSH Terms
- Aging
- Animals
- Basic-Leucine Zipper Transcription Factors
- Cervical Vertebrae
- Heme Oxygenase-1
- Intervertebral Disc Degeneration
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Oxidative Stress
Intracerebral hemorrhage (ICH)-induced brain edema and neurological deficits are greater in aged rats than in young rats. Complement activation and neutrophil infiltration contribute to brain injury after ICH. In this study, we investigated the effects of aging on activation of the complement cascade and neutrophil influx following ICH. Male Sprague-Dawley rats (3 or 18 months old) received an infusion of 100 microL autologous blood into right caudate. Rats were killed at 1, 3, 7, and 28 days after ICH and the brains were sampled for immunohistochemistry and Western blot analysis. Levels of complement factor C9 and clusterin were used as markers for complement activation, and myeloperoxidase (MPO) staining was performed to detect neutrophil infiltration. Western blot analysis showed that complement C9 and clusterin levels in ipsilateral basal ganglia after ICH were higher in aged rats than in young rats (p < 0.05). Immunohistochemistry showed there were more C9- and clusterin-positive cells around the hematoma in aged rats. However, MPO-positive cells in ipsilateral basal ganglia were fewer in aged rats (p < 0.05) after ICH. Our results suggest that ICH causes more severe complement activation and less neutrophil infiltration in aged rats. Clarification of the mechanisms of brain injury after ICH in the aging brain should help develop new therapeutic strategies for ICH.
MeSH Terms
- Aging
- Analysis of Variance
- Animals
- Basal Ganglia
- Brain Injuries
- Cerebral Hemorrhage
- Clusterin
- Complement Activation
- Complement C9
- Disease Models, Animal
- Functional Laterality
- Male
- Neutrophil Infiltration
- Peroxidase
- Rats
- Rats, Sprague-Dawley
- Time Factors
The present study examined spatial trends of perfluoroalkyl compounds (PFCs) in liver samples from 11 populations of ringed seals (Phoca hispida) in the Canadian Arctic from 2002 to 2005. Trophic position and relative carbon sources were compared by analyzing stable nitrogen and carbon isotopes in muscle samples. Geometric mean concentrations of total C9-C15 perfluorinated carboxylates (PFCAs) ranged from 8.8 to 84 ng/g wet weight, and C9-C11 PFCAs predominated. Perfluorooctane sulfonate was the dominant PFC measured, with concentrations ranging from 6.5 to 89 ng/g wet weight, contributing between 29 and 56% of the total PFC concentration. Overall, mean PFC concentrations were similar between populations, and differences were attributed largely to elevated levels in the Gjoa Haven (Rae Strait, central Canadian Arctic archipelago) and Inukjuak populations (eastern Hudson Bay) and to lower concentrations at Pangnirtung (Cumberland Sound, Baffin Island). Mean stable nitrogen isotope ratios ( /-95% confidence intervals) ranged from 14.7 per thousand ( /-0.3 per thousand) at Nain (Labrador) to 17.9 per thousand ( /-0.7 per thousand) at Gjoa Haven, suggesting that all populations were within the same trophic level. Stable carbon isotope ratios varied widely between the seal populations, ranging from -22.9 per thousand ( /-0.2 per thousand) at Gjoa Haven to -17.7 per thousand ( /-0.4 per thousand) at Nain. The delta13C ratios from Gjoa Haven were significantly more depleted than those for other populations and may suggest a terrestrially based carbon source. The depleted stable carbon isotope ratio may explain the elevated PFC concentrations in the Gjoa Haven population. Analysis of covariance indicated that delta13C was a significant covariable for seven of nine seal populations for which delta13C values were available. After adjusting for delta13C values, concentrations of most PFCs generally were statistically greater in the Grise Fiord, Qikiqtarjuaq, Arviat, and Nain populations.
MeSH Terms
- Aging
- Animals
- Arctic Regions
- Canada
- Carbon Isotopes
- Environmental Monitoring
- Environmental Pollutants
- Female
- Fluorocarbons
- Liver
- Male
- Nitrogen Isotopes
- Phoca
- Sex Characteristics
- Time Factors
Although chemoreception plays an important role in social organization of many lizards, only a few studies have examined the chemicals found in secretions used for intraspecific communication. We report the composition of the secretion of the femoral glands of males of the spiny-footed lizard (Acanthodactylus erythrurus). On the basis of mass spectra, obtained by GC/MS, we identified 45 lipophilic compounds, including several alcohols ranging from 10 to 29 carbon atoms (mainly hexacosanol and tetracosanol), steroids (mainly cholesterol and dehydrocholesterol), n-C9 to n-C20 carboxylic acids, esters of carboxylic acids, and minor components such as lactones, ketones, squalene and a-tocopherol. Some of these compounds are reported for the first time in lizards. Adult and subadult males differed in the composition of secretions, with C9 to C15 carboxylic acids being more abundant in younger than in older lizards, whereas C16 to C20 carboxylic acids were more abundant in older lizards. Also, older lizards had significant lower proportions of cholesterol and campesterol but higher proportions of dehydrocholesterol.
MeSH Terms
- Aging
- Animals
- Carboxylic Acids
- Exocrine Glands
- Gas Chromatography-Mass Spectrometry
- Lipid Metabolism
- Lizards
- Male
- Spain
The major route of folate turnover is by catabolic cleavage of the C9-N10 bond producing p-aminobenzoylglutamate (pABG) and its primary excretory form, p-acetamidobenzoylglutamate (ApABG). We hypothesize that total pABG (ApABG pABG) excretion parallels both the mass of body folate pools from which these catabolites originate and the folate-status indicators. The objective was to determine whether urinary folate catabolite excretion reflects body pool size and parallels the static and functional measures of folate status. Urinary folate catabolite excretion was measured in women (aged 60-85 y) consuming controlled amounts of folate for 14 wk. A low-folate diet (120 microg/d) was consumed (n = 33) for 7 wk, and then subjects were randomly assigned to consume either 200 (n = 14) or 400 (n = 16) microg folate/d. Urinary pABG and ApABG concentrations were measured by HPLC at 0, 7, and 14 wk. Urinary excretion of total pABG was significantly lower (P = 0.001) after depletion (73.9 /- 4.7 nmol/d) than at baseline (115 /- 12.7 nmol/d). This rate of decline (approximately 0.7% per day) is consistent with the kinetically measured rate of turnover of total body folate at moderate folate intakes. The average percentage increase in total pABG in response to folate repletion with 400 microg/d (75%) was significant (P = 0.02). Folate catabolite excretion was significantly (P = 0.0001) associated with serum and red blood cell folate, plasma homocysteine, and DNA hypomethylation after depletion and with serum folate (P = 0.001) and plasma homocysteine (P = 0.0002) after repletion with 400 microg folate/d. Total urinary pABG excretion reflects total body folate pool size and is a long-term indicator that parallels functional measures of folate status.
MeSH Terms
- 4-Aminobenzoic Acid
- Aged
- Aged, 80 and over
- Aging
- DNA Methylation
- Diet
- Erythrocytes
- Female
- Folic Acid
- Glutamates
- Homocysteine
- Humans
- Kinetics
- Middle Aged
- Nutritional Status
- para-Aminobenzoates
Apoliprotein J (apoJ)/clusterin has attracted considerable interest based on its inducibility in multiple injury processes and accumulation at sites of remodeling, regression, and degeneration. We therefore sought to investigate apoJ/clusterin's role in kidney aging, as this may reveal the accumulated effects of diminished protection. Aging mice deficient in apoJ/clusterin developed a progressive glomerulopathy characterized by the deposition of immune complexes in the mesangium. Up to 75% of glomeruli in apoJ/clusterin-deficient mice exhibited moderate to severe mesangial lesions by 21 months of age. Wild-type and hemizygous mice exhibited little or no glomerular pathology. In the apoJ/clusterin-deficient mice, immune complexes of immunoglobulin G (IgG), IgM, IgA, and in some cases C1q, C3, and C9 were detectable as early as 4 weeks of age. Electron microscopy revealed the accumulation of electron-dense material in the mesangial matrix and age-dependent formation of intramesangial tubulo-fibrillary structures. Even the most extensively damaged glomeruli showed no evidence of inflammation or necrosis. In young apoJ/clusterin-deficient animals, the development of immune complex lesions was accelerated by unilateral nephrectomy-induced hyperfiltration. Injected immune complexes localized to the mesangium of apoJ/clusterin-deficient but not wild-type mice. These results establish a protective role of apoJ/clusterin against chronic glomerular kidney disease and support the hypothesis that apoJ/clusterin modifies immune complex metabolism and disposal.
MeSH Terms
- Aging
- Animals
- Antigen-Antibody Complex
- Clusterin
- Complement System Proteins
- Disease Progression
- Glomerular Mesangium
- Glomerulonephritis, Membranoproliferative
- Glycoproteins
- Heterozygote
- Homozygote
- Immunoglobulins
- Kidney Glomerulus
- Mice
- Mice, Knockout
- Molecular Chaperones
- Nephrectomy
Muscular functions decline and muscle mass decreases during ageing. In the rat, there is a 27% decrease in muscle protein between 18 and 34 months of age. We examined age-related changes in the proteasome-dependent proteolytic pathway in rats at 4, 18, 24, 29 and 34 months of age. The three best characterised activities of the proteasome (chymotrypsin-like, trypsin-like and peptidylglutamyl peptide hydrolase) increased to 29 months and then decreased in the senescent animal. These variations in activity were accompanied by an identical change in the quantity of 20S proteasome measured by Western blot, whereas the S4 subunit of the 19S regulator and the quantity of ubiquitin-linked proteins remained constant. mRNA of subunits C3, C5, C9, and S4 increased in the senescent animal, but ubiquitin mRNA levels were unchanged. These findings suggest that the 20S proteasome may be partly responsible for the muscular atrophy observed during ageing in the rat.
MeSH Terms
- Aging
- Animals
- Atrophy
- Blotting, Western
- Body Weight
- Cysteine Endopeptidases
- Female
- Male
- Multienzyme Complexes
- Muscle, Skeletal
- Proteasome Endopeptidase Complex
- RNA, Messenger
- Rats
- Rats, Inbred Strains
- Ubiquitins
Total complement activity (CH50), and the protein levels of C1q, C4, C3, C5, C9, factor B and C1 inactivator were measured in the 1,130 sera obtained from healthy subjects aged between 20 and 79 years old. Increase in the levels of CH50, C1q, C4, C3, C5 and C9 and decrease of factor B were found in the older age group. The level of C1 inactivator showed little variation with aging.
MeSH Terms
- Adult
- Aged
- Aging
- Complement Activation
- Complement C3
- Complement C4
- Complement C5
- Complement C9
- Complement System Proteins
- Female
- Humans
- Male
- Middle Aged
The roles of complement levels and CFI activity in the regulation of chemotactic factor generation were evaluated in newborn and adult plasmas. Plasma samples were obtained from 19 healthy adults, 19 neonates, and 12 3-day-old infants. CFI levels were determined in all samples, chemotactic activity in 15 of the 19 adult and newborn samples, and complement levels in 10 of these 15. Compared to adult plasmas, CFI activity was higher in newborn and infant plasmas and chemotactic activity was lower. A close reciprocal relationship was shown between these two activities (r=-0.958). When corrected for the effects of CFI, the difference in chemotactic activity between newborns and adults disappeared. Mean levels of C1, C3, C4, C5, C3 to C9, CH50, factor B, and properdin were lower in newborn plasmas; however, C2 levels were higher. Partial correlations between these complement components and the chemotactic activity were of small magnitude and statistically not significant. These data suggest that higher CFI activity, rather than lower complement levels, accounts for most of the differences in chemotactic activity between newborn and adult plasma. (J Lab Clin Med 99:331, 1982.)
MeSH Terms
- Adult
- Aging
- Aminopeptidases
- Chemotactic Factors
- Chemotaxis
- Complement System Proteins
- Hemolysis
- Hot Temperature
- Humans
- Immune Sera
- Infant, Newborn
- Lysosomes
- Plasma
- Zymosan
Utilizing a monoclonal antibody (Poly C9-MA) to a neoantigen of the C9 portion of the membrane attack complex of complement (MAC), immunoelectron (IEM) and immunofluorescent (IF) microscopy were performed on kidney tissue from normal humans and patients with insulin-dependent diabetes mellitus (IDDM) and type II membrano-proliferative glomerulonephritis (MPGN II). Comparative studies were conducted using polyclonal antibodies to human C3, C5, IgG, IgA, and IgM. In normal human tissue, there was a close correlation between increasing chronologic age and the quantity of MAC deposited in the mesangial stalk, along the interstitial aspect of and within tubular basement membranes (TBMs) and in arteriolar walls. IF of kidney tissues from 12 patients with IDDM with varying degrees of mesangial expansion and glomerulosclerosis demonstrated a direct relationship between the degree of tissue damage and the amount of MAC deposited in the mesangium. IEM of three normal and four diabetic specimens revealed reaction product of Poly C9-MA on linear and circular membranous structures within the mesangium, TBMs, and vessel walls, and within the glomerular basement membranes (GBMs) in diabetic subjects. Evidence is presented that these structures, which have been previously described by routine electron microscopy, represent cellular debris in these loci on which Poly C9-MA has been deposited. In MPGN II, Poly C9-MA and C3 were distributed within subepithelial deposits, along either side of the dense deposits (DDs) within the GBMs and TBMs, and around circular masses of DDs within the mesangium.(ABSTRACT TRUNCATED AT 250 WORDS)
MeSH Terms
- Aging
- Complement Membrane Attack Complex
- Complement System Proteins
- Diabetes Mellitus, Type 1
- Fluorescent Antibody Technique
- Glomerulonephritis
- Humans
- In Vitro Techniques
- Kidney
- Microscopy, Electron
Immunoreactivity of vitronectin was investigated in 100 skin specimens from different body regions in 87 individuals of different ages using monoclonal and polyclonal anti-vitronectin antibodies in an avidin-biotin-peroxidase complex technique. Vitronectin immunoreactivity was found in conjunction with dermal elastic fibers in all subjects older than 13 years. No vitronectin immunostaining was detected in subjects younger than six years, suggesting deposition of vitronectin during late childhood or early adolescence. Using an immunogold staining procedure, vitronectin immunoreactivity was ultrastructurally localized to the periphery of elastic fibers. The blood level of vitronectin in 20 healthy newborns was 67% of the adult level, suggesting active biosynthesis already in the fetus. To investigate whether vitronectin is deposited as part of the SC5b-9 complex or as uncomplexed protein, the immunoreactivity of vitronectin was compared with that of C9, using monoclonal and polyclonal antibodies against the C9 neoantigen. Distinct C9 neoantigen immunoreactivity was demonstrated in association with dermal elastic fibers in human skin in adults but only in subjects older than 30 years. The intensity of C9 neoantigen immunoreactivity appeared to increase with age and was found to be stronger in sun-exposed skin than in sun-protected skin. These findings indicate that uncomplexed vitronectin is deposited during childhood or early adolescence and that terminal complement complexes (C5b-9 and/or SC5b-9) are deposited on elastic fibers later on in life. Hypothetically, the tissue form of vitronectin may be involved in the prevention of tissue damage in proximity to local complement activation. In addition, it may be physiologically important as substratum for cells, stimulating cell migration and anchorage.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens
- Child
- Child, Preschool
- Complement C9
- Elastic Tissue
- Glycoproteins
- Histological Techniques
- Humans
- Immunohistochemistry
- Infant
- Infant, Newborn
- Middle Aged
- Skin
- Vitronectin