Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
1.
Mol Psychiatry ; 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38871852

RESUMEN

The amyloid cascade hypothesis assumes that the development of Alzheimer's disease (AD) is driven by a self-perpetuating cycle, in which ß-amyloid (Aß) accumulation leads to Tau pathology and neuronal damages. A particular mutation (A673T) of the amyloid precursor protein (APP) was identified among Icelandic population. It provides a protective effect against Alzheimer- and age-related cognitive decline. This APP mutation leads to the reduced production of Aß with A2T (position in peptide sequence) change (Aßice). In addition, Aßice has the capacity to form protective heterodimers in association with wild-type Aß. Despite the emerging interest in Aßice during the last decade, the impact of Aßice on events associated with the amyloid cascade has never been reported. First, the effects of Aßice were evaluated in vitro by electrophysiology on hippocampal slices and by studying synapse morphology in cortical neurons. We showed that Aßice protects against endogenous Aß-mediated synaptotoxicity. Second, as several studies have outlined that a single intracerebral administration of Aß can worsen Aß deposition and cognitive functions several months after the inoculation, we evaluated in vivo the long-term effects of a single inoculation of Aßice or Aß-wild-type (Aßwt) in the hippocampus of transgenic mice (APPswe/PS1dE9) over-expressing Aß1-42 peptide. Interestingly, we found that the single intra-hippocampal inoculation of Aßice to mice rescued synaptic density and spatial memory losses four months post-inoculation, compared with Aßwt inoculation. Although Aß load was not modulated by Aßice infusion, the amount of Tau-positive neuritic plaques was significantly reduced. Finally, a lower phagocytosis by microglia of post-synaptic compounds was detected in Aßice-inoculated animals, which can partly explain the increased density of synapses in the Aßice animals. Thus, a single event as Aßice inoculation can improve the fate of AD-associated pathology and phenotype in mice several months after the event. These results open unexpected fields to develop innovative therapeutic strategies against AD.

2.
Hum Mol Genet ; 31(21): 3581-3596, 2022 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-35147158

RESUMEN

Pathogenesis of the inherited neurodegenerative disorder Huntington's disease (HD) is progressive with a long presymptomatic phase in which subtle changes occur up to 15 years before the onset of symptoms. Thus, there is a need for early, functional biomarker to better understand disease progression and to evaluate treatment efficacy far from onset. Recent studies have shown that white matter may be affected early in mutant HTT gene carriers. A previous study performed on 12 months old Ki140CAG mice showed reduced glutamate level measured by Chemical Exchange Saturation Transfer of glutamate (gluCEST), especially in the corpus callosum. In this study, we scanned longitudinally Ki140CAG mice with structural MRI, diffusion tensor imaging, gluCEST and magnetization transfer imaging, in order to assess white matter integrity over the life of this mouse model characterized by slow progression of symptoms. Our results show early defects of diffusion properties in the anterior part of the corpus callosum at 5 months of age, preceding gluCEST defects in the same region at 8 and 12 months that spread to adjacent regions. At 12 months, frontal and piriform cortices showed reduced gluCEST, as well as the pallidum. MT imaging showed reduced signal in the septum at 12 months. Cortical and striatal atrophy then appear at 18 months. Vulnerability of the striatum and motor cortex, combined with alterations of anterior corpus callosum, seems to point out the potential role of white matter in the brain dysfunction that characterizes HD and the pertinence of gluCEST and DTI as biomarkers in HD.


Asunto(s)
Enfermedad de Huntington , Sustancia Blanca , Animales , Ratones , Enfermedad de Huntington/diagnóstico por imagen , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Sustancia Blanca/patología , Imagen de Difusión Tensora/métodos , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Modelos Animales de Enfermedad , Ácido Glutámico
3.
EMBO J ; 38(16): e101302, 2019 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-31294477

RESUMEN

Collagen linearization is a hallmark of aggressive tumors and a key pathogenic event that promotes cancer cell invasion and metastasis. Cell-generated mechanical tension has been proposed to contribute to collagen linearization in tumors, but it is unknown whether other mechanisms play prominent roles in this process. Here, we show that the secretome of cancer cells is by itself able to induce collagen linearization independently of cell-generated mechanical forces. Among the tumor cell-secreted factors, we find a key role in this process for the matricellular protein WISP1 (CCN4). Specifically, WISP1 directly binds to type I collagen to promote its linearization in vitro (in the absence of cells) and in vivo in tumors. Consequently, WISP1-induced type I collagen linearization facilitates tumor cell invasion and promotes spontaneous breast cancer metastasis, without significantly affecting gene expression. Furthermore, higher WISP1 expression in tumors from cancer patients correlates with faster progression to metastatic disease and poor prognosis. Altogether, these findings reveal a conceptually novel mechanism whereby pro-metastatic collagen linearization critically depends on a cancer cell-secreted factor.


Asunto(s)
Neoplasias de la Mama/patología , Proteínas CCN de Señalización Intercelular/genética , Proteínas CCN de Señalización Intercelular/metabolismo , Colágeno Tipo I/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Metástasis de la Neoplasia , Trasplante de Neoplasias , Pronóstico , Factor de Crecimiento Transformador beta1/metabolismo , Regulación hacia Arriba
4.
Acta Neuropathol Commun ; 11(1): 66, 2023 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-37087498

RESUMEN

Alzheimer's disease (AD) is characterized by intracerebral deposition of abnormal proteinaceous assemblies made of amyloid-ß (Aß) peptides or tau proteins. These peptides and proteins induce synaptic dysfunctions that are strongly correlated with cognitive decline. Intracerebral infusion of well-defined Aß seeds from non-mutated Aß1-40 or Aß1-42 peptides can increase Aß depositions several months after the infusion. Familial forms of AD are associated with mutations in the amyloid precursor protein (APP) that induce the production of Aß peptides with different structures. The Aß Osaka (Aßosa mutation (E693Δ)) is located within the Aß sequence and thus the Aßosa peptides have different structures and properties as compared to non-mutated Aß1-42 peptides (Aßwt). Here, we wondered if a single exposure to this mutated Aß can worsen AD pathology as well as downstream events including cognition, cerebral connectivity and synaptic health several months after the inoculation. To answer this question we inoculated Aß1-42-bearing Osaka mutation (Aßosa) in the dentate gyrus of APPswe/PS1dE9 mice at the age of two months. Their cognition and cerebral connectivity were analyzed at 4 months post-inoculation by behavioral evaluation and functional MRI. Aß pathology as well as synaptic density were evaluated by histology. The impact of Aßosa peptides on synaptic health was also measured on primary cortical neurons. Remarkably, the intracerebral administration of Aßosa induced cognitive and synaptic impairments as well as a reduction of functional connectivity between different brain regions, 4 months post-inoculation. It increased Aß plaque depositions and increased Aß oligomers. This is the first study showing that a single, sporadic event as Aßosa inoculation can worsen the fate of the pathology and clinical outcome several months after the event. It suggests that a single inoculation of Aß regulates a large cascade of events for a long time.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ratones , Animales , Ratones Transgénicos , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Cognición , Mutación/genética , Modelos Animales de Enfermedad
5.
Nat Neurosci ; 26(4): 673-681, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36973511

RESUMEN

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience.


Asunto(s)
Mapeo Encefálico , Encéfalo , Ratas , Animales , Mapeo Encefálico/métodos , Consenso , Neuroimagen , Imagen por Resonancia Magnética/métodos
6.
Front Neuroinform ; 14: 24, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32547380

RESUMEN

Small-mammal neuroimaging offers incredible opportunities to investigate structural and functional aspects of the brain. Many tools have been developed in the last decade to analyse small animal data, but current softwares are less mature than the available tools that process human brain data. The Python package Sammba-MRI (SmAll-MaMmal BrAin MRI in Python; http://sammba-mri.github.io) allows flexible and efficient use of existing methods and enables fluent scriptable analysis workflows, from raw data conversion to multimodal processing.

7.
Genome Biol ; 21(1): 64, 2020 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-32160911

RESUMEN

BACKGROUND: How intestinal epithelial cells interact with the microbiota and how this is regulated at the gene expression level are critical questions. Smarcad1 is a conserved chromatin remodeling factor with a poorly understood tissue function. As this factor is highly expressed in the stem and proliferative zones of the intestinal epithelium, we explore its role in this tissue. RESULTS: Specific deletion of Smarcad1 in the mouse intestinal epithelium leads to colitis resistance and substantial changes in gene expression, including a striking increase of expression of several genes linked to innate immunity. Absence of Smarcad1 leads to changes in chromatin accessibility and significant changes in histone H3K9me3 over many sites, including genes that are differentially regulated upon Smarcad1 deletion. We identify candidate members of the gut microbiome that elicit a Smarcad1-dependent colitis response, including members of the poorly understood TM7 phylum. CONCLUSIONS: Our study sheds light onto the role of the chromatin remodeling machinery in intestinal epithelial cells in the colitis response and shows how a highly conserved chromatin remodeling factor has a distinct role in anti-microbial defense. This work highlights the importance of the intestinal epithelium in the colitis response and the potential of microbial species as pharmacological and probiotic targets in the context of inflammatory diseases.


Asunto(s)
Colitis/genética , ADN Helicasas/fisiología , Regulación de la Expresión Génica , Mucosa Intestinal/metabolismo , Animales , Colitis/microbiología , ADN Helicasas/genética , ADN Helicasas/metabolismo , Eliminación de Gen , Histonas/metabolismo , Ratones , Microbiota , Elementos Reguladores de la Transcripción
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA