APOA1
Apolipoprotein A-I precursor (Apo-AI) (ApoA-I) (Apolipoprotein A1) [Contains: Proapolipoprotein A-I (ProapoA-I); Truncated apolipoprotein A-I (Apolipoprotein A-I(1-242))]
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The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the [i]Lamp2[/i] gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch's membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD-namely, the accumulation of APOE, APOA1, clusterin, and vitronectin-adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch's membrane were reduced in [i]Lamp2[/i] knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.
MeSH Terms
- Aging
- Animals
- Basement Membrane
- Bruch Membrane
- Exocytosis
- Humans
- Lysosomal-Associated Membrane Protein 2
- Lysosomes
- Macular Degeneration
- Mice
- Mice, Knockout
- Phagocytosis
- Retina
- Retinal Pigment Epithelium
Keywords
- LAMP2
- aging
- lysosome
- retinal degeneration
Specific mutations in APOA1 gene lead to systemic, hereditary amyloidoses. In ApoA-I related amyloidosis involving the heart, amyloid deposits are mainly constituted by the 93-residue N-terminal region of the protein, here indicated as [1-93]ApoA-I. Oxidative stress is known to be an enhancing factor for protein aggregation. In healthy conditions, humans are able to counteract the formation and the effects of oxidative molecules. However, aging and atmospheric pollution increase the concentration of oxidative agents, such as metal ions. As the main effect of iron deregulation is proposed to be an increase in oxidative stress, we analysed the effects of iron on [1-93]ApoA-I aggregation. By using different biochemical approaches, we demonstrated that Fe(II) is able to reduce the formation of [1-93]ApoA-I fibrillar species, probably by stabilizing its monomeric form, whereas Fe(III) shows a positive effect on polypeptide fibrillogenesis. We hypothesize that, in healthy conditions, Fe(III) is reduced by the organism to Fe(II), thus inhibiting amyloid formation, whereas during ageing such protective mechanisms decline, thus exposing the organism to higher oxidative stress levels, which are also related to an increase in Fe(III). This alteration could contribute to the pathogenesis of amyloidosis.
MeSH Terms
- Aging
- Amyloidosis, Familial
- Apolipoprotein A-I
- Humans
- Iron
- Mutation
- Myocardium
- Oxidative Stress
- Peptides
- Plaque, Amyloid
- Protein Aggregation, Pathological
Keywords
- Amyloidosis
- ApoA-I
- Conformational analysis
- Iron
- Protein aggregation
Despite numerous developed drugs based on glucose metabolism interventions for treatment of age-related diseases such as diabetes neuropathies (DNs), DNs are still increasing in patients with type 1 or type 2 diabetes (T1D, T2D). We aimed to identify novel candidates in adipose tissue (AT) and pancreas with T2D for targeting to develop new drugs for DNs therapy. AT-T2D displayed 15 (e.g. SYT4 up-regulated and VGF down-regulated) and pancreas-T2D showed 10 (e.g. BAG3 up-regulated, VAV3 and APOA1 down-regulated) highly differentially expressed genes with neuronal functions as compared to control tissues. ELISA was blindly performed to measure proteins of 5 most differentially expressed genes in 41 human subjects. SYT4 protein was upregulated, VAV3 and APOA1 were down-regulated, and BAG3 remained unchanged in 1- Obese and 2- Obese-T2D without insulin, VGF protein was higher in these two groups as well as in group 3- Obese-T2D receiving insulin than 4-lean subjects. Interaction networks analysis of these 5 genes showed several metabolic pathways (e.g. lipid metabolism and insulin signaling). Pancreas is a novel site for APOA1 synthesis. VGF is synthesized in AT and could be considered as good diagnostic, and even prognostic, marker for age-induced diseases obesity and T2D. This study provides new targets for rational drugs development for the therapy of age-related DNs.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Adipose Tissue
- Adult
- Aged
- Analysis of Variance
- Apolipoprotein A-I
- Apoptosis Regulatory Proteins
- Diabetes Mellitus, Type 2
- Enzyme-Linked Immunosorbent Assay
- Female
- Gene Expression Profiling
- Gene Expression Regulation
- Humans
- Hypoglycemic Agents
- Insulin
- Male
- Middle Aged
- Nerve Growth Factors
- Neurons
- Obesity
- Pancreas
- Proto-Oncogene Proteins c-vav
- Reverse Transcriptase Polymerase Chain Reaction
- Synaptotagmins
Keywords
- age-related diabetes neuropathy
- aging
- diabetes
- obesity
- pancreas
DNA methylation variation has been implicated in memory, cognitive performance, and dementia. Plasma apolipoprotein-A1 (ApoA1) levels may act as a biomarker of age-associated cognitive performance and decline. To estimate the heritability of plasma ApoA1 protein levels; to examine DNA methylation variation within the APOA1 gene; and to investigate whether APOA1 methylation is associated with plasma ApoA1 levels and episodic memory performance. Heritability of ApoA1 protein levels in Older Australian Twins Study (OATS) was assessed using structural equation modelling. APOA1 methylation levels were assayed in two cohorts of cognitively normal older individuals. The methylation status of 12 CpGs in 24 twin pairs from OATS was assayed using the Illumina 450K methylation array. Candidate CpGs were assayed in 454 individuals from Sydney Memory and Ageing Study (Sydney MAS) using pyrosequencing. Regression analyses assessed associations between APOA1 methylation levels, ApoA1 plasma levels, and memory performance. No significant heritability was observed for ApoA1 protein levels. APOA1 candidate-gene analyses revealed CpG sites associated with memory performance in the twin study (p < 0.050). Replication of an association between methylation of a specific CpG (cg03010018) in APOA1 and memory performance was observed in Sydney MAS (β = -0.145, p = 0.010). Methylation of this CpG site was also significantly correlated with ApoA1 protein levels (β = 0.161, p = 0.019). However, no relationship between a composite memory domain score and methylation was observed (p = 0.389). Findings demonstrated that epigenetic control of APOA1 expression and DNA methylation levels are associated with episodic memory performance in older adults.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Apolipoprotein A-I
- Australia
- Cognition
- CpG Islands
- DNA Methylation
- Epigenomics
- Female
- Humans
- Male
- Memory, Episodic
- Neuropsychological Tests
- Regression Analysis
- Twins, Monozygotic
Keywords
- Aging
- DNA methylation
- apolipoprotein A1
- epigenomics
- episodic memory
Proteomic profiling of the pectoralis muscle of Thai indigenous chickens during growth period was analyzed using two-dimensional gel electrophoresis (2-DE) and matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF/MS). A total of 259, 161, 120 and 107 protein spots were found to be expressed in the chicken pectoralis muscles at 0, 3, 6 and 18 weeks of age, respectively. From these expressed proteins, five distinct protein spots were significantly associated with chicken age. These protein spots were characterized and showed homology with phosphoglycerate mutase 1 (PGAM1), apolipoprotein A1 (APOA1), triosephosphate isomerase 1 (TPI1), heat shock protein 25 kDa (HSP25) and fatty acid binding protein 3 (FABP3). These five protein spots were categorized as follows: (i) the expression levels of PGAM1 and TPI1 proteins were positively correlated with chicken aging (p<0.05), (ii) the expression levels of APOA1 and FABP3 proteins were negatively correlated with chicken aging (p<0.05) and (iii) the expression levels of the HSP25 protein were up- and down-regulated during growth period. Moreover, the mRNA expression levels of the FABP3 and HSP25 genes were significantly decreased in muscle during the growth period (p<0.05), whereas no significant changes of the PGAM1, TPI1 and APOA1 gene expression from the chicken muscle was observed. The identified proteins were classified as metabolic and stress proteins. This demonstrates a difference in energy metabolism and stress proteins between age groups and shows that proteomics is a useful tool to uncover the molecular basis of physiological differences in muscle during the growth period.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Apolipoprotein A-I
- Avian Proteins
- Chickens
- Electrophoresis, Gel, Two-Dimensional
- Fatty Acid-Binding Proteins
- Female
- Gene Expression Regulation, Developmental
- Heat-Shock Proteins
- Male
- Muscle, Skeletal
- Phosphoglycerate Mutase
- Polymerase Chain Reaction
- Proteome
- RNA, Messenger
- Triose-Phosphate Isomerase
Keywords
- chicken
- gene expression
- growth
- muscle
- proteome
To assess and compare the effects of short-term aromatase inhibition on glucose metabolism, lipid profile, and adipocytokine levels in young and elderly men. Ten elderly and nine young healthy men were randomized to receive letrozole 2.5 mg daily or placebo for 28 days in a crossover design. Both in young and elderly men, active treatment significantly increased serum testosterone ( 128 and 99%, respectively) and decreased estradiol levels (-41 and -62%, respectively). Fasting glucose and insulin levels decreased in young men after active intervention (-7 and -37%, respectively) compared with placebo. Leptin levels fell markedly in both age groups (-24 and -25%, respectively), while adiponectin levels were not affected by the intervention. Lipid profile was slightly impaired in both groups, with increasing low density lipoprotein-cholesterol levels ( 14%) in the younger age group and 10% lower levels of APOA1 in the elderly. A decline in IGF1 levels (-15%) was observed in the younger age group. No changes in weight or body mass index were observed in either young or old men. Short-term aromatase inhibition appears to affect glucose metabolism in young men, and lipid metabolism, including leptin secretion, in young and elderly men. Furthermore, the short period of exposure suggests that these changes might be mediated by direct effects of sex steroids rather than by changes in body composition.
MeSH Terms
- Administration, Oral
- Adult
- Aged
- Aged, 80 and over
- Aging
- Aromatase
- Aromatase Inhibitors
- Blood Glucose
- Cross-Over Studies
- Estradiol
- Humans
- Insulin
- Insulin-Like Growth Factor I
- Leptin
- Letrozole
- Luteinizing Hormone
- Male
- Nitriles
- Placebos
- Testosterone
- Triazoles
- Young Adult
The genes coding for apolipoprotein A1 (APOA1), apolipoprotein C3 ([[APOC3]]) and apolipoprotein A4 (APOA4) are tandemly organised within a short region on chromosome 11q23-q24. Polymorphisms of these genes have been extensively investigated in lipoprotein disorders and cardiovascular diseases, but poorly investigated in healthy ageing. The aim of this study was to describe possible modifications of the APOA1, [[APOC3]], and APOA4 gene pool by cross-sectional studies carried out in a healthy ageing population whose ages ranged from 18 to 109 years (800 subjects, 327 males and 473 females, free of clinically manifested disease, and with emato-chemical parameters in the norm). APOA1-MspI-RFLP (-75 nt from the transcription starting site), [[APOC3]]-SstI-RFLP (3'UTR, 3238 nt), and APOA4-HincII-RFLP (Asp127/Ser127) were analysed according to age and sex. A significant age-related variation of the APOA1 gene pool was observed in males. An analysis of the allele average effect exerted by APOA1-MspI-RFLP A/P alleles (Absence/Presence of the restriction site) on lipidemic parameters in 46-80 year old males showed that allele A decreased, while allele P significantly increased, serum LDL-cholesterol. Unexpectedly, the P allele was over-represented in the group of the oldest old subjects, thus giving evidence of another "genetic paradox of centenarians".
MeSH Terms
- Adolescent
- Adult
- Age Factors
- Aged
- Aging
- Apolipoprotein A-I
- Apolipoprotein C-III
- Apolipoproteins A
- Apolipoproteins C
- Child
- Chromosomes, Human, Pair 11
- Cross-Sectional Studies
- DNA
- Female
- Gene Frequency
- Genotype
- Humans
- Lipids
- Male
- Middle Aged
- Polymorphism, Genetic
- Sex Factors