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1.
Mol Cells ; 33(1): 35-41, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22134720

RESUMO

Obesity is associated with chronic low-grade inflammation, which contributes to systemic metabolic irregularities and obesity-linked metabolic disorders. Orosomucoid (ORM), an acute phase reactant protein, was shown to be produced in response to metabolic and inflammatory signals in the adipose tissue of obese mice, which protects them from severe inflammation and subsequent metabolic dysfunction. In this study, we examined whether there are site-specific differences between visceral and subcutaneous adipose tissue (VAT and SAT, respectively) ORM gene and protein expression from individuals with a wide range of obesity and the relationship between expressed and circulating ORM levels and measures of adiposity, insulin resistance, and pro- and anti-inflammatory markers and adipokines. The level of circulating ORM correlated positively with BMI, body fat mass, and serum leptin. It also correlated with fasting insulin, HOMA-IR values and C-reactive protein in men. There were no site-specific differences in ORM mRNA and protein expression between VAT and SAT, nor did we find a relationship between circulating ORM levels and its mRNA expression in either fat depot. We found that ORM mRNA expression correlated with mRNA expression of TNF-α, IL-6, and adiponectin in VAT, and with TNF-α and adiponectin in SAT. These observations are the first description linking adipose tissue ORM and pro- and anti-inflammatory molecules in humans. The close links of ORM and measures of adiposity, insulin resistance, and adipose tissue inflammation in humans reinforce previous experimental data and warrant further studies to explore a possible role of ORM in the pathogenesis of obesity-associated metabolic derangements.


Assuntos
Obesidade/metabolismo , Orosomucoide/metabolismo , RNA Mensageiro/metabolismo , Adiponectina/biossíntese , Adiponectina/sangue , Adolescente , Adulto , Idoso , Animais , Proteína C-Reativa/metabolismo , Feminino , Humanos , Interleucina-6/biossíntese , Leptina/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/genética , Orosomucoide/biossíntese , Orosomucoide/genética , RNA Mensageiro/genética , Gordura Subcutânea/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Adulto Jovem
2.
Am J Pathol ; 169(4): 1365-75, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17003492

RESUMO

Recapitulation of tau pathologies in an animal model has been a long-standing goal in neurodegenerative disease research. We generated transgenic (TgTauP301L) mice expressing a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTPD-17) mutation within the longest form of tau (2N, 4R). TgTauP301L mice developed florid pathology including neuronal pretangles, numerous Gallyas-Braak-positive neurofibrillary tangles, and glial fibrillary tangles in the frontotemporal areas of the cerebrum, in the brainstem, and to a lesser extent in the spinal cord. These features were accompanied by gliosis, neuronal loss, and cerebral atrophy. Accumulated tau was hyperphosphorylated, conformationally changed, ubiquitinated, and sarkosyl-insoluble, with electron microscopy demonstrating wavy filaments. Aged TgTauP301L mice exhibited impairment in hippocampally dependent and independent behavioral paradigms, with impairments closely related to the presence of tau pathologies and levels of insoluble tau protein. We conclude that TgTauP301L mice recreate the substantial phenotypic variation and spectrum of pathologies seen in FTDP-17 patients. Identification of genetic and/or environmental factors modifying the tau phenotype in these mice may shed light on factors modulating human tauopathies. These transgenic mice may aid therapeutic development for FTDP-17 and other diseases featuring accumulations of four-repeat tau, such as Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy.


Assuntos
Córtex Cerebral/patologia , Gliose/patologia , Transtornos da Memória/patologia , Doenças Neurodegenerativas/patologia , Neuroglia/patologia , Taurina/genética , Animais , Córtex Cerebral/química , Demência/genética , Demência/patologia , Modelos Animais de Doenças , Humanos , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Transgênicos , Mutação , Doenças Neurodegenerativas/genética , Neurônios/patologia , Fenótipo , Taurina/análise
3.
Proc Natl Acad Sci U S A ; 102(25): 8972-7, 2005 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-15951428

RESUMO

Gamma-secretase depends on presence of presenilins (PS), Nct, Aph-1, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-beta precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PS1 or PS2 genes shift APP cleavage from production of amyloid-beta (Abeta) 40 peptide to greater production of Abeta42. Although studies in PS1/PS2-deficient embryonic cells define overlapping activities for these proteins, in vivo complementation of PS1-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PS1 transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little Abeta40 or Abeta42 production, and FAD PS2 alleles support robust production of only Abeta42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a "gained" competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against gamma-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct gamma-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates.


Assuntos
Ácido Aspártico Endopeptidases/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Osso e Ossos/anormalidades , Osso e Ossos/patologia , Endopeptidases , Homozigoto , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mutação , Fragmentos de Peptídeos/metabolismo , Fenótipo , Presenilina-1 , Presenilina-2
4.
Am J Pathol ; 166(2): 521-31, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15681835

RESUMO

Missense mutations of the tau gene cause autosomal dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory loss between 10 to 12 months of age. These findings suggested that TgTauR406W mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimer's disease (AD).


Assuntos
Córtex Cerebral/metabolismo , Proteínas tau/biossíntese , Proteínas tau/genética , Tonsila do Cerebelo/metabolismo , Animais , Astrócitos/metabolismo , Comportamento Animal , Western Blotting , Encéfalo/metabolismo , Cricetinae , Vetores Genéticos , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Hipocampo/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Microscopia Eletrônica , Mutação , Mutação de Sentido Incorreto , Fosforilação , Príons/metabolismo , Conformação Proteica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Transgenes , Ubiquitina/metabolismo
5.
J Biol Chem ; 279(53): 55443-54, 2004 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-15459186

RESUMO

The PrP-like Doppel (Dpl) protein causes apoptotic death of cerebellar neurons in transgenic mice, a process prevented by expression of the wild type (wt) cellular prion protein, PrP(C). Internally deleted forms of PrP(C) resembling Dpl such as PrPDelta32-121 produce a similar PrP(C)-sensitive pro-apoptotic phenotype in transgenic mice. Here we demonstrate that these phenotypic attributes of wt Dpl, wt PrP(C), and PrPDelta132-121 can be accurately recapitulated by transfected mouse cerebellar granule cell cultures. This system was then explored by mutagenesis of the co-expressed prion proteins to reveal functional determinants. By this means, neuroprotective activity of wt PrP(C) was shown to be nullified by a deletion of the N-terminal charged region implicated in endocytosis and retrograde axonal transport (PrPDelta23-28), by deletion of all five octarepeats (PrPDelta51-90), or by glycine replacement of four octarepeat histidine residues required for selective binding of copper ions (Prnp"H/G"). In the case of Dpl, overlapping deletions defined a requirement for the gene interval encoding helices B and B' (DplDelta101-125). These data suggest contributions of copper binding and neuronal trafficking to wt PrP(C) function in vivo and place constraints upon current hypotheses to explain Dpl/PrP(C) antagonism by competitive ligand binding. Further implementation of this assay should provide a fuller understanding of the attributes and subcellular localizations required for activity of these enigmatic proteins.


Assuntos
Apoptose , Proteínas PrPC/genética , Proteínas PrPC/fisiologia , Príons/genética , Príons/fisiologia , Alelos , Animais , Morte Celular , Linhagem Celular Tumoral , Cerebelo/metabolismo , Mapeamento Cromossômico , Cobre , Análise Mutacional de DNA , Endocitose , Proteínas Ligadas por GPI , Deleção de Genes , Glicina/química , Proteínas de Fluorescência Verde/metabolismo , Íons , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência , Modelos Genéticos , Mutação , Neurônios/metabolismo , Neurônios/patologia , Fenótipo , Plasmídeos/metabolismo , Mutação Puntual , Proteínas PrPC/química , Príons/química , Ligação Proteica , Estrutura Terciária de Proteína , Transfecção , Transgenes
6.
Proc Natl Acad Sci U S A ; 100(24): 14193-8, 2003 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-14617772

RESUMO

Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-beta (Abeta) peptide. To explore this relationship in vivo, toxic-milk (txJ) mice with a mutant ATPase7b transporter favoring elevated Cu levels were analyzed in combination with the transgenic (Tg) CRND8 amyloid precursor protein mice exhibiting robust Abeta deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive txJ mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma Abeta levels. In addition, homozygosity for txJ increased survival of young TgCRND8 mice and lowered endogenous CNS Abeta at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the txJ mutation on CNS Abeta burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of Abeta peptide.


Assuntos
Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Cobre/metabolismo , Secretases da Proteína Precursora do Amiloide , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases , Encéfalo/metabolismo , ATPases Transportadoras de Cobre , Endopeptidases/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Fenótipo , Processamento de Proteína Pós-Traducional
7.
J Neurochem ; 86(3): 572-81, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12859671

RESUMO

Elevated levels of p25 and constitutive activation of CDK5 have been observed in AD brains. This has led to the hypothesis that increased p25 levels could promote neurofibrillary tangles (NFT) through CDK5-mediated hyperphosphorylation of tau, the principal component of NFTs. We examined p25 immunoreactivity in brains from sporadic and familial AD cases, as well as other neurologic diseases that exhibit NFT, such as Down's syndrome (DS), Pick's disease (Pick), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD). Neither the p25 immunoreactivity nor the p25/p35 ratio was elevated in the AD brains or in the other tauopathies (n = 34) compared with controls (n = 11). Although Abeta peptides have been suggested to activate calpain-mediated cleavage of p35 to p25 in cultured neurons, p25 levels in brains of TgCRND8 mice, which express high levels of brain Abeta peptides, were similar to those of non-Tg littermates. Our data suggest that high Abeta levels in brain do not activate p35 proteolysis, and p25 is unlikely to be a causative agent for NFT formation in AD or other tauopathies.


Assuntos
Doença de Alzheimer/enzimologia , Encéfalo/enzimologia , Proteínas do Tecido Nervoso/biossíntese , Doenças Neurodegenerativas/enzimologia , Emaranhados Neurofibrilares , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Química Encefálica , Quinase 5 Dependente de Ciclina , Quinases Ciclina-Dependentes/análise , Quinases Ciclina-Dependentes/biossíntese , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/análise
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