RESUMEN
INTRODUCTION: Diagnostic relevance of plasma amyloid ß (Aß) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aß42 and Aß40 in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers. METHODS: One thousand forty participants (417 amnestic MCI, 122 nonamnestic MCI, and 501 AD) from the Biomarker of AmyLoïd pepTide and AlZheimer's diseAse Risk multicenter prospective study with cognition, plasma, cerebrospinal fluid (CSF), and magnetic resonance imaging assessments were included. RESULTS: Plasma Aß1-42 and Aß1-40 were lower in AD (36.9 [11.7] and 263 [80] pg/mL) than in amnestic MCI (38.2 [11.9] and 269 [68] pg/mL) than in nonamnestic MCI (39.7 [10.5] and 272 [52] pg/mL), respectively (P = .01 for overall difference between groups for Aß1-42 and P = .04 for Aß1-40). Globally, plasma Aß1-42 correlated with age, Mini-Mental State Examination, and APOE ε4 allele. Plasma Aß1-42 correlated with all CSF biomarkers in MCI but only with CSF Aß42 in AD. DISCUSSION: Plasma Aß was associated with cognitive status and CSF biomarkers, suggesting the interest of plasma amyloid biomarkers for diagnosis purpose.
Asunto(s)
Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/sangre , Biomarcadores , Disfunción Cognitiva/sangre , Disfunción Cognitiva/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas de Estado Mental y Demencia/estadística & datos numéricos , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Among the different mechanisms underlying the etiopathogenesis of myotonic dystrophy type 1 (DM1), a backward reprogramming to a foetal splicing machinery is an interesting hypothesis. To address this possibility, Tau splicing, which is regulated during development and modified in DM1, was analyzed. Indeed, a preferential expression of the foetal Tau isoform, instead of the six normally found, is observed in adult DM1 brains. By using two cell lines, we show here that the cis-regulating elements necessary to generate the unique foetal Tau isoform are dispensable to reproduce the trans-dominant effect induced by DM1 mutation on Tau exon 2 inclusion. Our results suggest that the mis-splicing of Tau in DM1 is resulting from a disease-associated mechanism.
Asunto(s)
Empalme Alternativo , Feto/metabolismo , Distrofia Miotónica , Proteínas tau/metabolismo , Regiones no Traducidas 3' , Adulto , Línea Celular Tumoral , Exones , Feto/patología , Humanos , Distrofia Miotónica/genética , Distrofia Miotónica/metabolismo , Distrofia Miotónica/patología , Plásmidos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transfección , Proteínas tau/genéticaRESUMEN
Altered splicing of transcripts, including the insulin receptor (IR) and the cardiac troponin (cTNT), is a key feature of myotonic dystrophy type I (DM1). CELF and MBNL splicing factor members regulate the splicing of those transcripts. We have previously described an alteration of Tau exon 2 splicing in DM1 brain, resulting in the favored exclusion of exon 2. However, the factors required for alternative splicing of Tau exon 2 remain undetermined. Here we report a decreased expression of CELF family member and MBNL transcripts in DM1 brains as assessed by RT-PCR. By using cellular models with a control- or DM1-like splicing pattern of Tau transcripts, we demonstrate that ETR-3 promotes selectively the exclusion of Tau exon 2. These results together with the analysis of Tau exon 6 and IR exon 11 splicing in brain, muscle, and cell models suggest that DM1 splicing alteration of several transcripts involves various factors.
Asunto(s)
Empalme Alternativo/fisiología , Exones , Distrofia Miotónica/genética , Proteínas del Tejido Nervioso/fisiología , Proteínas de Unión al ARN/fisiología , Proteínas tau/metabolismo , Western Blotting/métodos , Encéfalo/metabolismo , Proteínas CELF , Línea Celular Tumoral , Electroforesis en Gel de Poliacrilamida/métodos , Exones/fisiología , Humanos , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Distrofia Miotónica/metabolismo , Neuroblastoma , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Transfección/métodos , Proteínas tau/genéticaRESUMEN
The synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) appears to possess an apoptotic activity superior to classical retinoids in vitro as in vivo. Numerous studies have shown that CD437-induced apoptosis is independent of its nuclear receptor activity, suggesting that CD437 might have a unique mechanism of action. The purpose of this study was to compare CD437- and all-trans retinoic acid (atRA)-induced cell death. CD437 provoked a rapid apoptotic phenotype immediately followed by secondary necrosis in RPMI 8226, U266 and L363 human myeloma cell lines. Nuclear apoptotic features were observed upon both CD437 and atRA treatments. In contrast, membrane blebbing and the subsequent formation of apoptotic bodies, a classical apoptotic event, was only observed upon atRA treatment. In addition, CD437, contrary to atRA, was unable to induce tissue transglutaminase (tTG), an intracellular enzyme involved in the formation of cross-linked protein polymers contributing to apoptotic morphological changes. Taken together, these data suggest that CD437 induces rapid but incomplete apoptotic phenotype in human myeloma cells.