RESUMEN
Active amyloid beta (Abeta) vaccination has been shown to be effective in clearing cerebral Abeta and improving cognitive function in mouse models of Alzheimer's disease (AD). The meningoencephalitis observed in AD vaccination trial was likely related to excessive T cell-mediated immunity caused by the immunogen Abeta(1-42). To avoid this toxicity, previous researchers have been using synthetic truncated Abeta derivatives that promote humoral immunity. In this study, we develop a novel adenovirus vaccine, which can express quadrivalent foldable Abeta(1-15) (4 x Abeta(15)) and gene adjuvant GM-CSF in vivo. Importantly, the 4 x Abeta(15) sequence includes an Abeta-specific B cell epitope but lacks the reported T cell epitope. The 4 x Abeta(15) adenovirus vaccine induces an Abeta-specific IgG1 predominant humoral immune response, and reduces brain Abeta deposition and cognition deficits in Tg2576 mice. Detection of IL-4 and IFN-gamma in restimulated splenocytes shows a significant Th2-polarized immune response. Stimulation of splenocytes with 4 x Abeta(15) peptides results in robust proliferative responses, whereas proliferation is absent after stimulation with full-length Abeta, which indicates that the 4 x Abeta(15) adenovirus vaccine does not induce Abeta-specific T cellular immune response. Thus, our results raise the possibility that adenovirus vector encoding 4 x Abeta(15) would be a promising candidate for future AD vaccination program.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/metabolismo , Trastornos Mentales/terapia , Linfocitos T/inmunología , Vacunación/métodos , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Análisis de Varianza , Animales , Conducta Animal , Citocinas/líquido cefalorraquídeo , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática/métodos , Vectores Genéticos/fisiología , Humanos , Aprendizaje por Laberinto/fisiología , Trastornos Mentales/etiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Tiempo de Reacción , Linfocitos T/metabolismoRESUMEN
Mitochondrial dysfunction may play an important role in the pathogenesis of ageing and age-neurodegenerative diseases such as Alzheimer's disease (AD). Platelet mitochondrial membrane potential (reflected by measurement of JC-1 fluorescence ratio) and adenosine 5'-triphosphate (ATP) contents of 24 moderate probable AD patients, 20 age-matched control subjects and 20 young control subjects were measured. Also, a beta-amyloid peptide (Abeta)-induced damage model of platelets was established. After the addition of Abeta, platelet JC-1 fluorescence ratio and ATP content of platelets were measured in 16 AD patients, 20 aged and 20 young control subjects. Young control subjects had higher JC-1 fluorescence ratio than both AD patients and aged control subjects. No significant differences in platelet ATP contents were found among AD patients, aged and young control subjects. After the addition of Abeta, platelet JC-1 fluorescence ratio and ATP content of aged and young control subjects lowered markedly, but no obvious decrease of platelet JC-1 fluorescence ratio of AD patients was found compared with those of aged and young control subjects. Decrease of platelet JC-1 fluorescence ratio of aged control subjects was lower than that of young control subjects following the addition of Abeta. These results indicated that mitochondrial dysfunction may occur during ageing and platelet mitochondria of AD patients and aged subjects showed a tolerance to Abeta-induced damage. Therefore, blood platelets might serve as a biomarker for detection of mitochondrial function and age-related disease.
Asunto(s)
Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Plaquetas/metabolismo , Mitocondrias/metabolismo , Adenosina Trifosfato/análisis , Adenosina Trifosfato/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Análisis de Varianza , Bencimidazoles/análisis , Biomarcadores/análisis , Plaquetas/ultraestructura , Carbocianinas/análisis , Estudios de Casos y Controles , Células Cultivadas , Femenino , Humanos , Masculino , Potencial de la Membrana Mitocondrial , Microscopía Fluorescente , Persona de Mediana Edad , Fragmentos de PéptidosRESUMEN
In the present study, ovariectomized Sprague-Dawley rats were used to mimic the pathological changes of post-menopausal females with genistein and estradiol benzoate (EB) as substitutes for endogenous estradiol. Measurements of hippocampal ATP content, mitochondrial ATP content and the rate of mitochondrial ATP synthesis in the hippocampus indicated that after ovariectomy, brain energy metabolism of the rats presented a transient change in hippocampal ATP content which was significant from the 6th to the 8th day after ovariectomy. The change on the 6th day was the most noteworthy. Mitochondrial ATP content and the rate of mitochondrial ATP synthesis of the hippocampus were also lowered. However, after using EB or genistein, the three indicators returned to normal. It is suggested that mitochondrial dysfunction may play a key role in Alzheimer's disease (AD) of the post-menopausal female, and may serve as the target for endogenous estrogen and exogenous phytoestrogen. In addition, genistein, which possesses the properties of estrogen but not its side effects such as carcinogenicity, could reverse the bioenergetic defects of ovariectomized rats and perhaps be used as a substitute for estradiol to prevent or treat central neurodegeneration in post-menopausal women.
Asunto(s)
Mitocondrias/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Neuronas/metabolismo , Ovariectomía , Adenosina Trifosfato/análisis , Adenosina Trifosfato/biosíntesis , Adenosina Trifosfato/metabolismo , Animales , Modelos Animales de Enfermedad , Estradiol/administración & dosificación , Estradiol/análogos & derivados , Femenino , Genisteína/administración & dosificación , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Inyecciones Subcutáneas , Mitocondrias/efectos de los fármacos , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/prevención & control , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: This experiment evaluated the perinatal hypoxic effect on the retina of offspring of the ovoviviparous fish. ANIMAL STUDIED: The ovoviviparous fish Xiphophorous maculates was used for the experiment. PROCEDURE: The mothers were kept in a hypoxic environment of 3.5% oxygen for 6 h, starting 30 h before hatching. Subsequently, the retinae of the offspring were fixed, sectioned at 6 microm and evaluated microscopically from the age of 1 to 35 days. RESULTS: Degeneration of the outer nuclear layer of the retina was noted on the 3rd day and severe retinal degeneration was observed on the 35th day. Immunocytochemistry confirmed apoptosis by TUNEL reaction. There was no difference in neovascularization, as revealed by vascular endothelial growth factor, between controls (group 1) and hypoxic fish (group 2). CONCLUSIONS: Perinatal hypoxia could have long-lasting effects on the central nervous system in some species.
Asunto(s)
Ciprinodontiformes , Enfermedades de los Peces/etiología , Hipoxia/veterinaria , Degeneración Retiniana/veterinaria , Animales , Apoptosis , Enfermedades de los Peces/patología , Hipoxia/complicaciones , Etiquetado Corte-Fin in Situ/veterinaria , Distribución Aleatoria , Degeneración Retiniana/etiología , Degeneración Retiniana/patología , Neovascularización Retiniana/veterinaria , Especificidad de la Especie , Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Senescence-accelerated mice (SAM) strains are useful models to understand the mechanisms of age-dependent degeneration. In this study, measurements of the mitochondrial membrane potential (Deltapsi(m)) of platelets and the Adenosine 5(')-triphosphate (ATP) content of hippocampi and platelets were made, and platelet mitochondria were observed in SAMP8 (faster aging mice) and SAMR1 (aging resistant control mice) at 2, 6 and 9 months of age. In addition, an Abeta-induced (Amyloid beta-protein) damage model of platelets was established. After the addition of Abeta, the Deltapsi(m) of platelets of SAMP8 at 1 and 6 months of age were measured. We found that platelet Deltapsi(m), and hippocampal and platelet ATP content of SAMP8 mice decreased at a relatively early age compared with SAMR1. The platelets of 6 month-old SAMP8 showed a tolerance to Abeta-induced damages. These results suggest that mitochondrial dysfunction might be one of the mechanisms leading to age-associated degeneration in SAMP mice at an early age and the platelets could serve as a biomarker for detection of mitochondrial function and age related disease.