A2M
Alpha-2-macroglobulin precursor (Alpha-2-M) (C3 and PZP-like alpha-2-macroglobulin domain-containing protein 5) [CPAMD5] [FWP007]
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Alpha-2-macroglobulin (A2M) is a glycosylated broad spectrum inhibitor of numerous proteases, including those involved in blood coagulation. Glycosylation characteristics can affect protein structure and function. This study compares glycosylation characteristics of A2M in newborn umbilical cord (NUCP) and adult pooled plasmas. Peptide N-Glycosidase F treatment was used to evaluate the total N-glycan content of the molecules. Neuraminidase treatment, and affinity for Ricinus Communis Agglutinin I were used to examine terminal sialic acid and galactose content, respectively. Two-dimensional (2D) electrophoresis was used to determine charge-related isoform profiles and fluorophore-assisted carbohydrate electrophoresis (FACE) was used to characterize N-glycan profiles. Results revealed no difference in total N-glycan mass, however, a statistically significant difference was shown in the change in charge associated with sialic acid loss in the NUCP A2M population. 2D electrophoresis indicated a lower pI range for NUCP A2M isoforms. In addition, NUCP A2M displayed a trend toward higher terminal galactose quantities than adult A2M. FACE revealed an increased abundance of more branched, higher molecular weight glycans in NUCP A2M. These differences in glycan branching and charged residues may impact A2M receptor-based clearance and thus could be responsible for the increased A2M concentration seen in NUCP, and newborns.
MeSH Terms
- Adult
- Aging
- Electrophoresis, Gel, Two-Dimensional
- Glycosylation
- Humans
- Infant, Newborn
- Polysaccharides
- Pregnancy-Associated alpha 2-Macroglobulins
- Protein Isoforms
- Umbilical Cord
Keywords
- Alpha-2-macroglobulin
- Glycosylation
- Newborn
- Plasma
Age-associated renal fibrosis is related with renal function decline during aging. Imbalance between accumulation and degradation of extracellular matrix is key feature of fibrosis. In this study, RNA-sequencing (RNA-Seq) results based on next-generation sequencing (NGS) data were analyzed to identify key proteins that change during aging and calorie restriction (CR). Among the changed genes, A2M and MMP2, which are known to interact, exhibited the highest between centrality (BC) and degree values when analyzed by protein-protein interaction (PPI). Both mRNA and protein levels of MMP2 and A2M were increased during aging. Furthermore, the interaction between MMP2 and A2M was verified by immunoprecipitation and immunohistochemistry. MMP2 activity was further measured under the presence or absence of A2M-MMP2 interaction. MMP2 activity, which was increased under the absence of A2M-MMP2 interaction, was significantly decreased under the presence of interactions in aged kidney. We further hypothesized that the interaction between A2M-MMP2 played a role in the inactivation of MMP2 leading to accumulation of ECM including collagen type I and IV. Aged kidney showed highly accumulated MMP2 substrate proteins despite of increased MMP2 protein expression and CR blunted these accumulation. Additional [i]in vivo[/i] analysis revealed that the signal transducer and activator of transcription (STAT) 3 transcriptional factor was significantly increased thus increasing A2M expression during aging. STAT3 activating cytokines were also highly increased in aged kidney. In conclusion, the results of the present study indicate that A2M-MMP2 interaction has a role in age-associated renal ECM accumulation and in the suppression such fibrosis by CR.
Keywords
- A2M
- Aging
- Gerotarget
- MMP2
- extracellular matrix
- renal fibrosis
We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Brain
- Calcium-Binding Proteins
- Cerebrovascular Circulation
- Cognition Disorders
- Extracellular Matrix Proteins
- Female
- Humans
- Independent Living
- Longitudinal Studies
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Neuropsychological Tests
- Polymorphism, Single Nucleotide
- Positron-Emission Tomography
Keywords
- Alzheimer’s disease
- magnetic resonance imaging
- positron emission tomography
- single nucleotidepolymorphism
Risk alleles for age-related diseases are expected to decrease in frequency in the population strata of increasing age. Consistent with this hypothesis, earlier studies showed a depletion of the Alzheimer's disease risk factor APOE*epsilon4 in long-lived individuals (LLIs). To evaluate whether this observation also holds for a previously suggested Alzheimer's disease risk haplotype in the A2M gene, we analyzed this particular haplotype in 1042 German LLIs (aged 95-100 years) and 1040 younger individuals (aged 60-75 years). Our results show a significant depletion of this haplotype in LLIs, thus confirming it as a mortality factor in the elderly. Consequently, our data support an involvement of the suggested A2M risk haplotype in the pathogenesis of Alzheimer's disease and adds new evidence to the risk-allele depletion hypothesis.
MeSH Terms
- Aged
- Aged, 80 and over
- Alzheimer Disease
- Apolipoproteins E
- Genetic Predisposition to Disease
- Haplotypes
- Humans
- Longevity
- alpha-Macroglobulins
Zinc maintains brain functions because involved in glutaminergic transmission, in antioxidant response and in conferring biological activity to brain enzymes and growth factors. Zinc turnover is mediated by Metallothioneins (MT) which regulate the intracellular free zinc ions [Zn](i). Alterations in zinc homeostasis are associated to various brain dysfunctions, including brain inflammatory status, but little is known about its implication in the aging brain and neurodegeneration. Literature data in experimental animals suggest that zinc dyshomeostasis may occur in aging associated to a decline in brain functions. One of the causes may be an altered homeostasis of MT and other zinc-binding proteins, such as alpha2 macroglobulin (A2M), which are of protection against stress and inflammation during young/adult age but turn into being harmful in aging. In fact, despite total brain zinc content is unchanged in the brain of aged animals, with respect to the young/adult, the activity of some zinc dependent enzymes is impaired and large amount of zinc has been found in the core of Alzheimer's disease senile plaques. The role played by MT and A2M is reported in ageing and Alzheimer's disease and on some polymorphisms of A2M and inflammatory genes (cytokines and their receptors) because some of them may be affected by zinc, via MT homeostasis.
MeSH Terms
- Aged
- Aging
- Alzheimer Disease
- Brain
- Homeostasis
- Humans
- Nerve Degeneration
- Polymorphism, Genetic
- Zinc
- alpha-Macroglobulins
The study subjects were 192 overweight and obese Thais (BMI > 25.00 kg/m2), and 103 Thai controls (BMI = 18.50-24.99 kg/m2), whose ages ranged from 18-60 years. All subjects were evaluated for serum Alpha-2-macroglobulin (A2M), globulin, albumin concentration, and polymorphic variation in the A2M gene. Serum A2M and albumin were significantly lower in the overweight/obese group (P < 0.05). For the overweight/obese and control group, the median ages were 38 and 37 years, serum A2M 200.2; 252.0 (mg/L), albumin 4.4; 4.5 (g/dL), and globulin 3.0; 2.95 (g/dL), respectively. A2M deletion polymorphism genotyping showed no association between A2M deletion polymorphism and the two groupings. At serum A2M concentration < 250 mg/L, there was no relationship between A2M deletion polymorphism and age. Serum A2M had a significant negative correlation with age in all subjects (R = 0.09, P < 0.05). The results did not support the hypothesis that A2M deletion polymorphism is associated with a low A2M concentration in overweight/obese subjects. However, serum A2M had a significant negative correlation with age; serum A2M can possibly be used to indicate the aging of cells in vivo, including the brain. Further studies are needed to investigate other A2M genes located on chromosome 12 to prove A2M gene polymorphism's association with low serum A2M and aging.
MeSH Terms
- Adolescent
- Adult
- Aging
- DNA
- Electrophoresis, Polyacrylamide Gel
- Female
- Gene Deletion
- Genotype
- Humans
- Logistic Models
- Male
- Middle Aged
- Obesity
- Odds Ratio
- Polymorphism, Genetic
- Serum Albumin
- Thailand
- alpha-Macroglobulins
alpha2-macroglobulin (alpha(2)M) is an abundant plasma protein similar in structure and function to a group of proteins called alpha-macroglobulins. alpha(2)M is also produced in the brain where it binds multiple extracellular ligands and is internalized by neurons and astrocytes. In the brain of Alzheimer's disease (AD) patients, alpha(2)M has been localized to diffuse amyloid plaques. alpha(2)M also binds soluble beta-amyloid, of which it mediates degradation. However, an excess of alpha(2)M can also have neurotoxic effects. Based on genetic evidence, is now recognized as one of the two confirmed late onset AD genes. As for the three early onset genes (the amyloid beta-protein precursor and the two presenilins) and for the other late onset gene (ApoE), DNA polymorphisms in the A2M gene associated with AD result in significantly increased accumulation of amyloid plaques in AD brains. These data support an important role for A2M in AD etiopathology.
MeSH Terms
- Age of Onset
- Aging
- Alzheimer Disease
- Humans
- Polymorphism, Genetic
- Structure-Activity Relationship
- alpha-Macroglobulins