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Post by Max on Jun 12, 2005 8:03:19 GMT -5
Decreased retinoid receptor expression with age
Inadequate retinoid status has often been described as occurring with aging. Several studies performed in animals have described the crucial incidence of age-related hypo-functioning of retinoid and thyroid signalling pathways, particularly in the brain. RARgamma expression was significantly decreased in elderly versus young subjects [1]. A significantly decreased retinoid receptor expression in human subjects after exposure to (Ro)accutane is here suggested.
In hypothyroid subjects, the concentration of TSH was elevated, and dramatically low T3 and T4 concentrations were associated with a decrease in the expression of TR beta. Expression of RAR alpha and RAR gamma significantly decreased in hypothyroid versus control subjects [2].
Further decreased levels of retinoid metabolites with age in certain ares of the human brain
In studied human brains, frontal lobes, but not occipital lobes, exhibited an age-related decline in retinol, total tocopherols, total xanthophylls and total carotenoids [3].
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Post by Max on Jun 12, 2005 8:03:42 GMT -5
References:
[1] Feart C, Pallet V, Boucheron C, Higueret D, Alfos S, Letenneur L, Dartigues JF, Higueret P. Aging affects the retinoic acid and the triiodothyronine nuclear receptor mRNA expression in human peripheral blood mononuclear cells. (2005) Eur J Endocrinol. Mar;152(3):449-58
[2] Feart C, Vallortigara J, Higueret D, Gatta B, Tabarin A, Enderlin V, Higueret P, Pallet V. Decreased expression of retinoid nuclear receptor (RAR alpha and RAR gamma) mRNA determined by real-time quantitative RT-PCR in peripheral blood mononuclear cells of hypothyroid patients. (2005) J Mol Endocrinol. Jun;34(3):849-58.
[3] Craft NE, Haitema TB, Garnett KM, Fitch KA, Dorey CK. Carotenoid, tocopherol, and retinol concentrations in elderly human brain. (2004) J Nutr Health Aging. 8(3):156-62.
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Post by Max on Jul 1, 2005 17:35:34 GMT -5
Mech Ageing Dev. 2005 Feb;126(2):333-9. Related Articles, Links
Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study.
Stessman J, Maaravi Y, Hammerman-Rozenberg R, Cohen A, Nemanov L, Gritsenko I, Gruberman N, Ebstein RP.
Department of Geriatric Rehabilitation, Hadassah Hospital, Hebrew University Medical Center, Mt. Scopus, Jerusalem.
In an exploratory study, 11 common polymorphisms were examined for contributing to longevity including: apolipoprotein E (apoE), methylenetetrahydrofolate reductase (MTHFR), cathepsin D (CAD), superoxide dismutase 2 (SOD2), angiotensinogen (AGT) and insulin-like growth factor 2 (IGF2), Leiden factor 7, p53 oncogene, dopamine D4 receptor (DRD4) and the serotonin transporter (SERT). Genotype and allele frequencies of these genes were compared in 224 older (75 years) Jewish Jerusalem residents of Ashkenazi ethnicity to a group of 441 younger subjects (22 years). Nominally significant results provide suggestive evidence in the Ashkenazi group that apoE, MHTFR, SOD2, IGF2 ApaI, and factor VII are risk factors for a single outcome, survival to 75. Overall, the more genetically homogenous Ashkenazi ethnic group showed evidence for association in five genes examined suggesting that future studies in this population would gainfully focus on this ethnic group.
PMID: 15621215 [PubMed - indexed for MEDLINE]
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Post by Max on Jul 1, 2005 17:37:08 GMT -5
Neurobiol Aging. 2005 Jun 15; [Epub ahead of print] Related Articles, Links
Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype.
Reger MA, Watson GS, Frey WH 2nd, Baker LD, Cholerton B, Keeling ML, Belongia DA, Fishel MA, Plymate SR, Schellenberg GD, Cherrier MM, Craft S.
Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, 1660 S, Columbian Way, S182-GRECC, Seattle, WA 98108, USA; Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Raising insulin acutely in the periphery and in brain improves verbal memory. Intranasal insulin administration, which raises insulin acutely in the CNS without raising plasma insulin levels, provides an opportunity to determine whether these effects are mediated by central insulin or peripheral processes. Based on prior research with intravenous insulin, we predicted that the treatment response would differ between subjects with (varepsilon4+) and without (varepsilon4-) the APOE-varepsilon4 allele. On separate mornings, 26 memory-impaired subjects (13 with early Alzheimer's disease and 13 with amnestic mild cognitive impairment) and 35 normal controls each underwent three intranasal treatment conditions consisting of saline (placebo) or insulin (20 or 40IU). Cognition was tested 15min post-treatment, and blood was acquired at baseline and 45min after treatment. Intranasal insulin treatment did not change plasma insulin or glucose levels. Insulin treatment facilitated recall on two measures of verbal memory in memory-impaired varepsilon4- adults. These effects were stronger for memory-impaired varepsilon4- subjects than for memory-impaired varepsilon4+ subjects and normal adults. Unexpectedly, memory-impaired varepsilon4+ subjects showed poorer recall following insulin administration on one test of memory. These findings suggest that intranasal insulin administration may have therapeutic benefit without the risk of peripheral hypoglycemia and provide further evidence for apolipoprotein E (APOE) related differences in insulin metabolism.
PMID: 15964100 [PubMed - as supplied by publisher]
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Post by Max on Jul 1, 2005 17:38:28 GMT -5
J Neurochem. 2004 Feb;88(3):623-34. Related Articles, Links
A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes.
Liang Y, Lin S, Beyer TP, Zhang Y, Wu X, Bales KR, DeMattos RB, May PC, Li SD, Jiang XC, Eacho PI, Cao G, Paul SM.
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285, USA.
Apolipoprotein E (apoE) is an important protein involved in lipoprotein clearance and cholesterol redistribution. ApoE is abundantly expressed in astrocytes in the brain and is closely linked to the pathogenesis of Alzheimer's disease (AD). We report here that small molecule ligands that activate either liver X receptors (LXR) or retinoid X receptor (RXR) lead to a dramatic increase in apoE mRNA and protein expression as well as secretion of apoE in a human astrocytoma cell line (CCF-STTG1 cells). Examination of primary mouse astrocytes also revealed significant induction of apoE mRNA, and protein expression and secretion following incubation with LXR/RXR agonists. Moreover, treatment of mice with a specific synthetic LXR agonist T0901317 resulted in up-regulation of apoE mRNA and protein in both hippocampus and cerebral cortex, indicating that apoE expression in brain can be up-regulated by LXR agonists in vivo. Along with a dramatic induction of ABCA1 cholesterol transporter expression, these ligands effectively mediate cholesterol efflux in both CCF-STTG1 cells and mouse astrocytes in the presence or absence of apolipoprotein AI (apoAI). Our studies provide strong evidence that small molecule LXR/RXR agonists can effectively mediate apoE synthesis and secretion as well as cholesterol homeostasis in astrocytes. LXR/RXR agonists may have significant impact on the pathogenesis of multiple neurological diseases, including AD.
PMID: 14720212 [PubMed - indexed for MEDLINE]
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Post by Max on Jul 1, 2005 17:47:55 GMT -5
J Biol Chem. 2004 Jan 30;279(5):3862-8. Epub 2003 Oct 29. Related Articles, Links
Astroglial regulation of apolipoprotein E expression in neuronal cells. Implications for Alzheimer's disease.
Harris FM, Tesseur I, Brecht WJ, Xu Q, Mullendorff K, Chang S, Wyss-Coray T, Mahley RW, Huang Y.
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94141-9100, USA.
Although apolipoprotein (apo) E is synthesized in the brain primarily by astrocytes, neurons in the central nervous system express apoE, albeit at lower levels than astrocytes, in response to various physiological and pathological conditions, including excitotoxic stress. To investigate how apoE expression is regulated in neurons, we transfected Neuro-2a cells with a 17-kilobase human apoE genomic DNA construct encoding apoE3 or apoE4 along with upstream and downstream regulatory elements. The baseline expression of apoE was low. However, conditioned medium from an astrocytic cell line (C6) or from apoE-null mouse primary astrocytes increased the expression of both isoforms by 3-4-fold at the mRNA level and by 4-10-fold at the protein level. These findings suggest that astrocytes secrete a factor or factors that regulate apoE expression in neuronal cells. The increased expression of apoE was almost completely abolished by incubating neurons with U0126, an inhibitor of extracellular signal-regulated kinase (Erk), suggesting that the Erk pathway controls astroglial regulation of apoE expression in neuronal cells. Human neuronal precursor NT2/D1 cells expressed apoE constitutively; however, after treatment of these cells with retinoic acid to induce differentiation, apoE expression diminished. Cultured mouse primary cortical and hippocampal neurons also expressed low levels of apoE. Astrocyte-conditioned medium rapidly up-regulated apoE expression in fully differentiated NT2 neurons and in cultured mouse primary cortical and hippocampal neurons. Thus, neuronal expression of apoE is regulated by a diffusible factor or factors released from astrocytes, and this regulation depends on the activity of the Erk kinase pathway in neurons.
PMID: 14585838 [PubMed - indexed for MEDLINE]
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Post by Max on Jul 1, 2005 17:51:15 GMT -5
Oncogene. 2004 Sep 16;23(42):7053-66. Related Articles, Links
Enhanced retinoid-induced apoptosis of MDA-MB-231 breast cancer cells by PKC inhibitors involves activation of ERK.
Pettersson F, Couture MC, Hanna N, Miller WH.
Lady Davis Institute for Medical Research, McGill University, 3755 Cote-Ste-Catherine Rd, Montreal, Quebec, Canada H3T 1E2.
Retinoids are vitamin A derivatives, which cause growth inhibition, differentiation and/or apoptosis in various cell types, including some breast cancer cells. In general, estrogen receptor (ER)-positive cells are retinoic acid (RA) sensitive, whereas ER-negative cells are resistant. In this report, we show that ER-negative MDA-MB-231 cells are strongly growth inhibited by retinoids in combination with a PKC inhibitor. While neither RA nor GF109203X (GF) has a significant growth inhibitory effect in these cells, RA+GF potently suppress proliferation. We found that RA+GF induce apoptosis, as shown by an increase in fragmented DNA, Annexin-V-positive cells and caspase-3 activation. Apoptosis was also induced by GF in combination with two synthetic retinoids. Expression of phosphorylated as well as total PKC was decreased by GF and this was potentiated by RA. In addition, treatment with GF caused a strong and sustained activation of ERK1/2 and p38-MAPK, as well as a weaker activation of JNK. Importantly, inhibition of ERK but not p38 or JNK suppressed apoptosis induced by RA+GF, indicating that activation of ERK is specifically required. In support of this novel finding, the ability of other PKC inhibitors to cause apoptosis in combination with RA correlates with ability to cause sustained activation of ERK.
PMID: 15273718 [PubMed - indexed for MEDLINE]
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Post by Max on Jul 1, 2005 17:59:13 GMT -5
J Neurosci. 1996 Dec 1;16(23):7550-6. Related Articles, Links
Transcription factor AP-2 regulates human apolipoprotein E gene expression in astrocytoma cells.
Garcia MA, Vazquez J, Gimenez C, Valdivieso F, Zafra F.
Centro de Biologia Molecular Severo Ochoa, Facultad de Ciencias, Universidad Autonoma de Madrid, Spain.
Apolipoprotein E (apoE), one of the major plasma lipoproteins, also is expressed in a variety of cell types, including the glial cells of the nervous system. apoE is involved in processes of degeneration and regeneration after nerve lesions as well as in the pathogenesis of Alzheimer's disease (AD). Glial synthesis of apoE is activated in response to injury both in the peripheral and central nervous system. We now report that the activity of the proximal apoE promoter in astrocytes is upregulated by cAMP and retinoic acid, which act synergistically. Sequence analysis of the apoE promoter indicated the presence of several AP-2 consensus sequences that could mediate the stimulatory effect of cAMP and retinoic acid. The possible functional role of AP-2 was examined by cotransfection of AP-2-deficient HepG2 cells with an apoE promoter construct and a human AP-2 expression construct. Cotransfection with AP-2 significantly elevated apoE promoter activity. DNase I footprinting technique revealed the existence of two binding sites for recombinant AP-2 in regions from -48 to -74 and from -107 to -135 of the apoE promoter. Mutations in these regions markedly impaired the trans-stimulatory effect of AP-2. These results indicate the existence of functional AP-2 sites in the promoter region of apoE that could contribute to the complex regulation of this gene in developmental, degenerative, and regenerative processess of the nervous system.
PMID: 8922411 [PubMed - indexed for MEDLINE]
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Post by Max on Jul 1, 2005 18:10:57 GMT -5
J Clin Invest. 1997 Jul 15;100(2):310-20. Related Articles, Links
Neuronal cell death in Alzheimer's disease correlates with apoE uptake and intracellular Abeta stabilization.
LaFerla FM, Troncoso JC, Strickland DK, Kawas CH, Jay G.
Department of Virology, Jerome H. Holland Laboratory, Rockville, Maryland 20855, USA.
The brains of individuals with Alzheimer's disease (AD) are characterized by extracellular deposition of beta-amyloid protein (Abeta), intracellular neurofibrillary tangles, and loss of neurons. To study molecular markers associated with dying cells in the AD brain, in situ DNA labeling techniques were used to visualize cells with DNA fragmentation. We observed that intracellular accumulation of apolipoprotein E (apoE) is correlated with the detection of intracellular Abeta-like immunoreactivity within the same cytoplasmic granules, suggesting that uptake of lipids may have stabilized the hydrophobic Abeta protein within the cell. These apoE-containing neurons also exhibit high expression of a cell surface receptor, gp330, which is known to bind apoE. Cells containing significant nuclear DNA fragmentation express the highest level of cell surface gp330. Extracellular deposition of Abeta is detected only upon neuronal cell death, initially as halos of Abeta immunoreactivity around individual dying neurons, and subsequently as Abeta plaques containing numerous neuronal cell ghosts. Based on our in situ analysis of nuclear DNA fragmentation, we conclude that neuronal cell death likely occurs before the extracellular deposition of Abeta in AD brains.
PMID: 9218507 [PubMed - indexed for MEDLINE]
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Post by adfa on May 4, 2010 9:53:00 GMT -5
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Post by adfa on May 4, 2010 9:53:39 GMT -5
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Post by afda on May 5, 2010 6:59:42 GMT -5
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Post by dfdf on May 5, 2010 9:57:42 GMT -5
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Post by srdthtrt on Sept 7, 2018 20:01:30 GMT -5
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