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1.
J Biol Chem ; 291(53): 27204-27218, 2016 12 30.
Artículo en Inglés | MEDLINE | ID: mdl-27793990

RESUMEN

The risk of Alzheimer's disease (AD) is highly dependent on apolipoprotein-E (apoE) genotype. The reasons for apoE isoform-selective risk are uncertain; however, both the amounts and structure of human apoE isoforms have been hypothesized to lead to amyloidosis increasing the risk for AD. To address the hypothesis that amounts of apoE isoforms are different in the human CNS, we developed a novel isoform-specific method to accurately quantify apoE isoforms in clinically relevant samples. The method utilizes an antibody-free enrichment step and isotope-labeled physiologically relevant lipoprotein particle standards produced by immortalized astrocytes. We applied this method to a cohort of well characterized clinical samples and observed the following findings. The apoE isoform amounts are not different in cerebrospinal fluid (CSF) from young normal controls, suggesting that the amount of apoE isoforms is not the reason for risk of amyloidosis prior to the onset of advanced age. We did, however, observe an age-related increase in both apoE isoforms. In contrast to normal aging, the presence of amyloid increased apoE3, whereas apoE4 was unchanged or decreased. Importantly, for heterozygotes, the apoE4/apoE3 isoform ratio was increased in the CNS, although the reverse was true in the periphery. Finally, CSF apoE levels, but not plasma apoE levels, correlated with CSF ß-amyloid levels. Collectively, these findings support the hypothesis that CNS and peripheral apoE are separate pools and differentially regulated. Furthermore, these results suggest that apoE mechanisms for the risk of amyloidosis and AD are related to an interaction between apoE, aging, and the amount of amyloid burden.


Asunto(s)
Amiloidosis/sangre , Amiloidosis/líquido cefalorraquídeo , Apolipoproteína E3/análisis , Apolipoproteína E4/análisis , Biomarcadores/análisis , Encéfalo/metabolismo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Secuencia de Aminoácidos , Amiloidosis/diagnóstico , Astrocitos/citología , Astrocitos/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Demencia/sangre , Demencia/líquido cefalorraquídeo , Demencia/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
2.
Electrophoresis ; 33(24): 3745-55, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23161654

RESUMEN

Apolipoprotein E (ApoE) is a major lipid carrier protein. In humans, ApoE is expressed in three polymorphic isoforms, which are encoded by three different alleles APOE2, APOE3, and APOE4. In the brains of Alzheimer's disease (AD) patients, each one of these three allelic isoforms is found in several "isoelectric" protein isoforms (qPI), i.e. protein isoforms resulting from PTMs altering the net charge (q) of the polypeptide. AD is a complex disease in which multiple causes and several risk factors affect the onset and disease outcome. A major risk factor for AD is ApoE4; therefore, it is important to characterize the different ApoE qPIs. We have implemented a detergent-based method for isolation and quantitation of protein isoforms, and we found differences in the solubility of protein isoforms depending on the type of solvent used. In this manuscript, we describe these methods and applied them to young human-ApoE targeted replacement mice. Our results indicate that there are no significant differences in the hippocampus proteome of these mice as a function of the APOE genotype.


Asunto(s)
Apolipoproteína E3/biosíntesis , Apolipoproteína E4/biosíntesis , Proteoma/análisis , Análisis de Varianza , Animales , Apolipoproteína E3/análisis , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/análisis , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Creatina Quinasa/análisis , Creatina Quinasa/química , Creatina Quinasa/metabolismo , Electroforesis en Gel Bidimensional , Genotipo , Hipocampo/química , Hipocampo/metabolismo , Humanos , Ratones , Ratones Transgénicos , Fosfopiruvato Hidratasa/análisis , Fosfopiruvato Hidratasa/química , Fosfopiruvato Hidratasa/metabolismo , Isoformas de Proteínas , Proteoma/química , Proteoma/genética , Proteoma/metabolismo , Proteómica/métodos , Solubilidad
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