Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
Neurobiol Aging ; 36(7): 2241-2247, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25911278

RESUMEN

Endogenous murine amyloid-ß peptide (Aß) is expressed in most Aß precursor protein (APP) transgenic mouse models of Alzheimer's disease but its contribution to ß-amyloidosis remains unclear. We demonstrate ∼ 35% increased cerebral Aß load in APP23 transgenic mice compared with age-matched APP23 mice on an App-null background. No such difference was found for the much faster Aß-depositing APPPS1 transgenic mouse model between animals with or without the murine App gene. Nevertheless, both APP23 and APPPS1 mice codeposited murine Aß, and immunoelectron microscopy revealed a tight association of murine Aß with human Aß fibrils. Deposition of murine Aß was considerably less efficient compared with the deposition of human Aß indicating a lower amyloidogenic potential of murine Aß in vivo. The amyloid dyes Pittsburgh Compound-B and pentamer formyl thiophene acetic acid did not differentiate between amyloid deposits consisting of human Aß and deposits of mixed human-murine Aß. Our data demonstrate a differential effect of murine Aß on human Aß deposition in different APP transgenic mice. The mechanistically complex interaction of human and mouse Aß may affect pathogenesis of the models and should be considered when models are used for translational preclinical studies.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Encéfalo/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Ratones Transgénicos
2.
Neurobiol Aging ; 32(12): 2324.e1-6, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20970889

RESUMEN

APPPS1 transgenic mice develop amyloid-ß 42 (Aß42)-driven early-onset cerebral ß-amyloidosis. Stereological analysis of neocortical neuron number in groups of 2-, 10-, and 17-month-old APPPS1 mice did not reveal any changes compared with wild-type control animals despite massive amyloid-ß (Aß) load and disrupted cytoarchitecture. However, in subregions with high neuron density such as the granule cell layer of the dentate gyrus, modest but significant neuron loss was found, reminiscent of findings in previously published mouse models with late onset cerebral ß-amyloidosis and predominant amyloid-ß 40 (Aß40) expression.


Asunto(s)
Precursor de Proteína beta-Amiloide/genética , Degeneración Nerviosa/metabolismo , Neuritas/patología , Neuronas/patología , Placa Amiloide/metabolismo , Presenilina-1/genética , Factores de Edad , Animales , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Neuritas/metabolismo , Neuronas/metabolismo , Placa Amiloide/genética , Placa Amiloide/patología , Distribución Aleatoria , Índice de Severidad de la Enfermedad
3.
Nat Neurosci ; 12(11): 1361-3, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19838177

RESUMEN

In Alzheimer's disease, microglia cluster around beta-amyloid deposits, suggesting that these cells are important for amyloid plaque formation, maintenance and/or clearance. We crossed two distinct APP transgenic mouse strains with CD11b-HSVTK mice, in which nearly complete ablation of microglia was achieved for up to 4 weeks after ganciclovir application. Neither amyloid plaque formation and maintenance nor amyloid-associated neuritic dystrophy depended on the presence of microglia.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Antígeno CD11b/genética , Microglía/fisiología , Peste/patología , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antivirales/efectos adversos , Antivirales/farmacología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Ganciclovir/efectos adversos , Ganciclovir/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Humanos , Inyecciones Intraarticulares/métodos , Masculino , Ratones , Ratones Transgénicos , Microglía/efectos de los fármacos , Microscopía Inmunoelectrónica/métodos , Mutación , Distrofias Neuroaxonales/etiología , Distrofias Neuroaxonales/metabolismo , Distrofias Neuroaxonales/patología , Presenilina-1/genética , Timidina Quinasa/genética
4.
Am J Pathol ; 175(1): 271-82, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19556514

RESUMEN

Alzheimer's disease is characterized by numerous pathological abnormalities, including amyloid beta (Abeta) deposition in the brain parenchyma and vasculature. In addition, intracellular Abeta accumulation may affect neuronal viability and function. In this study, we evaluated the effects of different forms of Abeta on cognitive decline by analyzing the behavioral induction of the learning-related gene Arc/Arg3.1 in three different transgenic mouse models of cerebral amyloidosis (APPPS1, APPDutch, and APP23). Following a controlled spatial exploration paradigm, reductions in both the number of Arc-activated neurons and the levels of Arc mRNA were seen in the neocortices of depositing mice from all transgenic lines (deficits ranging from 14 to 26%), indicating an impairment in neuronal encoding and network activation. Young APPDutch and APP23 mice exhibited intracellular, granular Abeta staining that was most prominent in the large pyramidal cells of cortical layer V; these animals also had reductions in levels of Arc. In the dentate gyrus, striking reductions (up to 58% in aged APPPS1 mice) in the number of Arc-activated cells were found. Single-cell analyses revealed both the proximity to fibrillar amyloid in aged mice, and the transient presence of intracellular granular Abeta in young mice, as independent factors that contribute to reduced Arc levels. These results provide evidence that two independent Abeta pathologies converge in their impact on cognitive function in Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Proteínas del Citoesqueleto/genética , Aprendizaje/fisiología , Proteínas del Tejido Nervioso/genética , Envejecimiento/patología , Enfermedad de Alzheimer/fisiopatología , Precursor de Proteína beta-Amiloide/genética , Animales , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Citoplasma/química , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Matriz Extracelular , Expresión Génica , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Ratones , Ratones Transgénicos , Microscopía Confocal , Neuronas/metabolismo , Neuronas/patología , ARN Mensajero/análisis
5.
Am J Pathol ; 172(6): 1520-8, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18467698

RESUMEN

The hippocampus in Alzheimer's disease is burdened with amyloid plaques and is one of the few locations where neurogenesis continues throughout adult life. To evaluate the impact of amyloid-beta deposition on neural stem cells, hippocampal neurogenesis was assessed using bromodeoxyuridine incorporation and doublecortin staining in two amyloid precursor protein (APP) transgenic mouse models. In 5-month-old APP23 mice prior to amyloid deposition, neurogenesis showed no robust difference relative to wild-type control mice, but 25-month-old amyloid-depositing APP23 mice showed significant increases in neurogenesis compared to controls. In contrast, 8-month-old amyloid-depositing APPPS1 mice revealed decreases in neurogenesis compared to controls. To study whether alterations in neurogenesis are the result of amyloid-induced changes at the level of neural stem cells, APPPS1 mice were crossed with mice expressing green fluorescence protein (GFP) under a central nervous system-specific nestin promoter. Eight-month-old nestin-GFP x APPPS1 mice exhibited decreases in quiescent nestin-positive astrocyte-like stem cells, while transient amplifying progenitor cells did not change in number. Strikingly, both astrocyte-like and transient-amplifying progenitor cells revealed an aberrant morphologic reaction toward congophilic amyloid-deposits. A similar reaction toward the amyloid was no longer observed in doublecortin-positive immature neurons. Results provide evidence for a disruption of neural stem cell biology in an amyloidogenic environment and support findings that neurogenesis is differently affected among various transgenic mouse models of Alzheimer's disease.


Asunto(s)
Amiloidosis/patología , Hipocampo/patología , Neuronas/patología , Placa Amiloide/patología , Células Madre/patología , Envejecimiento/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Animales Recién Nacidos , Diferenciación Celular , Proliferación Celular , Cruzamientos Genéticos , Modelos Animales de Enfermedad , Femenino , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Proteínas de Filamentos Intermediarios/genética , Proteínas de Filamentos Intermediarios/metabolismo , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Nestina , Neuronas/fisiología , Células Madre/fisiología
6.
J Neurosci ; 28(16): 4283-92, 2008 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-18417708

RESUMEN

Microglial cells aggregate around amyloid plaques in Alzheimer's disease, but, despite their therapeutic potential, various aspects of their reactive kinetics and role in plaque pathogenesis remain hypothetical. Through use of in vivo imaging and quantitative morphological measures in transgenic mice, we demonstrate that local resident microglia rapidly react to plaque formation by extending processes and subsequently migrating toward plaques, in which individual transformed microglia somata remain spatially stable for weeks. The number of plaque-associated microglia increased at a rate of almost three per plaque per month, independent of plaque volume. Larger plaques were surrounded by larger microglia, and a subset of plaques changed in size over time, with an increase or decrease related to the volume of associated microglia. Far from adopting a more static role, plaque-associated microglia retained rapid process and membrane movement at the plaque/glia interface. Microglia internalized systemically injected amyloid-binding dye at a much higher rate in the vicinity of plaques. These results indicate a role for microglia in plaque maintenance and provide a model with multiple targets for therapeutic intervention.


Asunto(s)
Amiloide/metabolismo , Microglía/metabolismo , Microglía/patología , Placa Amiloide/metabolismo , Placa Amiloide/patología , Amiloide/genética , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Placa Amiloide/genética , Factores de Tiempo
7.
Eur J Nucl Med Mol Imaging ; 35 Suppl 1: S70-4, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18270700

RESUMEN

To study Alzheimer's disease (AD), a variety of mouse models has been generated through the overexpression of the amyloid precursor protein and/or the presenilins harboring one or several mutations found in familial AD. With aging, these mice develop several lesions similar to those of AD, including diffuse and neuritic amyloid deposits, cerebral amyloid angiopathy, dystrophic neurites and synapses, and amyloid-associated neuroinflammation. Other characteristics of AD, such as neurofibrillary tangles and nerve cell loss, are not satisfactorily reproduced in these models. Mouse models that recapitulate only specific aspects of AD pathogenesis are of great advantage when deciphering the complexity of the disease and can contribute substantially to diagnostic and therapeutic innovations. Incomplete mouse models have been key to the development of Abeta42-targeted therapies, as well as to the current understanding of the interrelationship between cerebral beta-amyloidosis and tau neurofibrillary lesions, and are currently being used to develop novel diagnostic agents for in vivo imaging.


Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Artefactos , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Placa Amiloide/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/patología , Animales , Encéfalo/patología , Humanos , Ratones , Ratones Transgénicos
8.
Am J Pathol ; 171(6): 2012-20, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18055549

RESUMEN

Alzheimer's disease presents morphologically with senile plaques, primarily made of extracellular amyloid-beta (A beta) deposits, and neurofibrillary lesions, which consist of intracellular aggregates of hyperphosphorylated tau protein. To study the in vivo induction of tau pathology, dilute brain extracts from aged A beta-depositing APP23 transgenic mice were intracerebrally infused in young B6/P301L tau transgenic mice. Six months after the infusion, tau pathology was induced in the injected hippocampus but also in brain regions well beyond the injection sites such as the entorhinal cortex and amygdala, areas with neuronal projection to the injection site. No or only modest tau induction was observed when brain extracts from aged nontransgenic control mice and aged tau-depositing B6/P301L transgenic mice were infused. To further study A beta-induced tau lesions B6/P301L tau transgenic mice were crossed with APP23 mice. Although A beta deposition in double-transgenic mice did not differ from single APP23 transgenic mice, double-transgenic mice revealed increased tau pathology compared to single B6/P301L tau transgenic mice predominately in areas with high A beta plaque load. The present results suggest that both extract-derived A beta species and deposited fibrillary A beta can induce the formation of tau neurofibrillary pathology. The observation that infused A beta can trigger the tau pathology in the absence of A beta deposits provides an explanation for the discrepancy between the neuroanatomical location of A beta deposits and the development and spreading of tau lesions in Alzheimer's disease brain.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/toxicidad , Precursor de Proteína beta-Amiloide/toxicidad , Tauopatías/genética , Tauopatías/patología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/administración & dosificación , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/administración & dosificación , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Química Encefálica , Extractos Celulares/administración & dosificación , Extractos Celulares/toxicidad , Femenino , Ratones , Ratones Transgénicos , Tauopatías/metabolismo , Proteínas tau/genética
9.
EMBO Rep ; 7(9): 940-6, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16906128

RESUMEN

We have generated a novel transgenic mouse model on a C57BL/6J genetic background that coexpresses KM670/671NL mutated amyloid precursor protein and L166P mutated presenilin 1 under the control of a neuron-specific Thy1 promoter element (APPPS1 mice). Cerebral amyloidosis starts at 6-8 weeks and the ratio of human amyloid (A)beta42 to Abeta40 is 1.5 and 5 in pre-depositing and amyloid-depositing mice, respectively. Consistent with this ratio, extensive congophilic parenchymal amyloid but minimal amyloid angiopathy is observed. Amyloid-associated pathologies include dystrophic synaptic boutons, hyperphosphorylated tau-positive neuritic structures and robust gliosis, with neocortical microglia number increasing threefold from 1 to 8 months of age. Global neocortical neuron loss is not apparent up to 8 months of age, but local neuron loss in the dentate gyrus is observed. Because of the early onset of amyloid lesions, the defined genetic background of the model and the facile breeding characteristics, APPPS1 mice are well suited for studying therapeutic strategies and the pathomechanism of amyloidosis by cross-breeding to other genetically engineered mouse models.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Modelos Animales de Enfermedad , Proteínas de la Membrana/genética , Neocórtex/metabolismo , Fragmentos de Péptidos/metabolismo , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Angiopatía Amiloide Cerebral/genética , Cognición , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/patología , Fragmentos de Péptidos/genética , Presenilina-1
10.
J Cell Sci ; 117(Pt 2): 189-98, 2004 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-14676273

RESUMEN

Histone macroH2A1.2 and the murine heterochromatin protein 1, HP1 beta, have both been implicated in meiotic sex chromosome inactivation (MSCI) and the formation of the XY-body in male meiosis. In order to get a closer insight into the function of histone macroH2A1.2 we have investigated the localisation of macroH2A1.2 in surface spread spermatocytes from normal male mice and in oocytes of XX and XYTdym1 mice. Oocytes of XYTdym1 mice have no XY-body or MSCI despite having an XY chromosome constitution, so the presence or absence of 'XY-body' proteins in association with the X and/or Y chromosome of these oocytes enables some discrimination between potential functions of XY-body located proteins. We demonstrate here that macroH2A1.2 localises to the X and Y chromatin of spermatocytes as they condense to form the XY-body but is not associated with the X and Y chromatin of XYTdym1 early pachytene oocytes. MacroH2A1.2 and HP1 beta co-localise to autosomal pericentromeric heterochromatin in spermatocytes. However, the two proteins show temporally and spatially distinct patterns of association to X and Y chromatin.


Asunto(s)
Proteínas Cromosómicas no Histona/metabolismo , Histonas/metabolismo , Cromatina Sexual/metabolismo , Animales , Cromatina/metabolismo , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/genética , Emparejamiento Cromosómico/genética , Emparejamiento Cromosómico/fisiología , Cromosomas/metabolismo , Femenino , Histonas/genética , Masculino , Meiosis/fisiología , Ratones , Oocitos/citología , Oocitos/metabolismo , Cromatina Sexual/genética , Cromosomas Sexuales/genética , Espermatocitos/citología , Espermatocitos/metabolismo , Cromosoma Y/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...