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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.
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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.
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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 GlutámicoRESUMEN
Glutamate is the amino acid with the highest cerebral concentration. It plays a central role in brain metabolism. It is also the principal excitatory neurotransmitter in the brain and is involved in multiple cognitive functions. Alterations of the glutamatergic system may contribute to the pathophysiology of many neurological disorders. For example, changes of glutamate availability are reported in rodents and humans during Alzheimer's and Huntington's diseases, epilepsy as well as during aging. Most studies evaluating cerebral glutamate have used invasive or spectroscopy approaches focusing on specific brain areas. Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) is a recently developed imaging technique that can be used to study relative changes in glutamate distribution in the entire brain with higher sensitivity and at higher resolution than previous techniques. It thus has strong potential clinical applications to assess glutamate changes in the brain. High field is a key condition to perform gluCEST images with a meaningful signal to noise ratio. Thus, even if some studies started to evaluate gluCEST in humans, most studies focused on rodent models that can be imaged at high magnetic field. In particular, systematic characterization of gluCEST contrast distribution throughout the whole brain has never been performed in humans or non-human primates. Here, we characterized for the first time the distribution of the gluCEST contrast in the whole brain and in large-scale networks of mouse lemur primates at 11.7 Tesla. Because of its small size, this primate can be imaged in high magnetic field systems. It is widely studied as a model of cerebral aging or Alzheimer's disease. We observed high gluCEST contrast in cerebral regions such as the nucleus accumbens, septum, basal forebrain, cortical areas 24 and 25. Age-related alterations of this biomarker were detected in the nucleus accumbens, septum, basal forebrain, globus pallidus, hypophysis, cortical areas 24, 21, 6 and in olfactory bulbs. An age-related gluCEST contrast decrease was also detected in specific neuronal networks, such as fronto-temporal and evaluative limbic networks. These results outline regional differences of gluCEST contrast and strengthen its potential to provide new biomarkers of cerebral function in primates.
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Ácido Glutámico , Imagen por Resonancia Magnética , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Mapeo Encefálico , Ácido Glutámico/metabolismo , Humanos , Imagen por Resonancia Magnética/métodos , PrimatesRESUMEN
Measures of resting-state functional connectivity allow the description of neuronal networks in humans and provide a window on brain function in normal and pathological conditions. Characterizing neuronal networks in animals is complementary to studies in humans to understand how evolution has modelled network architecture. The mouse lemur (Microcebus murinus) is one of the smallest and more phylogenetically distant primates as compared to humans. Characterizing the functional organization of its brain is critical for scientists studying this primate as well as to add a link for comparative animal studies. Here, we created the first functional atlas of mouse lemur brain and describe for the first time its cerebral networks. They were classified as two primary cortical networks (somato-motor and visual), two high-level cortical networks (fronto-parietal and fronto-temporal) and two limbic networks (sensory-limbic and evaluative-limbic). Comparison of mouse lemur and human networks revealed similarities between mouse lemur high-level cortical networks and human networks as the dorsal attentional (DAN), executive control (ECN), and default-mode networks (DMN). These networks were however not homologous, possibly reflecting differential organization of high-level networks. Finally, cerebral hubs were evaluated. They were grouped along an antero-posterior axis in lemurs while they were split into parietal and frontal clusters in humans.
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Atlas como Asunto , Encéfalo/diagnóstico por imagen , Cheirogaleidae , Red en Modo Predeterminado/diagnóstico por imagen , Adulto , Animales , Atención/fisiología , Encéfalo/fisiología , Red en Modo Predeterminado/fisiología , Función Ejecutiva/fisiología , Femenino , Neuroimagen Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiología , DescansoRESUMEN
Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a mouse default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. RSN spatial specificity was enhanced in datasets acquired at higher field strength, with cryoprobes, in ventilated animals, and under medetomidine-isoflurane combination sedation. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.
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Encéfalo/fisiología , Conectoma/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Red Nerviosa/fisiología , Animales , Encéfalo/diagnóstico por imagen , Conectoma/normas , Femenino , Procesamiento de Imagen Asistido por Computador/normas , Imagen por Resonancia Magnética/normas , Masculino , Ratones , Ratones Endogámicos C57BL , Red Nerviosa/diagnóstico por imagen , Reproducibilidad de los ResultadosRESUMEN
The gray mouse lemur (Microcebus murinus) is a small prosimian of growing interest for studies of primate biology and evolution, and notably as a model organism of brain aging. As brain atlases are essential tools for brain investigation, the objective of the current work was to create the first 3D digital atlas of the mouse lemur brain. For this, a template image was constructed from in vivo magnetic resonance imaging (MRI) data of 34 animals. This template was then manually segmented into 40 cortical, 74 subcortical and 6 cerebro-spinal fluid (CSF) regions. Additionally, we generated probability maps of gray matter, white matter and CSF. The template, manual segmentation and probability maps, as well as imaging tools used to create and manipulate the template, can all be freely downloaded. The atlas was first used to automatically assess regional age-associated cerebral atrophy in a cohort of mouse lemurs previously studied by voxel based morphometry (VBM). Results based on the atlas were in good agreement with the VBM ones, showing age-associated atrophy in the same brain regions such as the insular, parietal or occipital cortices as well as the thalamus or hypothalamus. The atlas was also used as a tool for comparative neuroanatomy. To begin with, we compared measurements of brain regions in our MRI data with histology-based measures from a reference article largely used in previous comparative neuroanatomy studies. We found large discrepancies between our MRI-based data and those of the reference histology-based article. Next, regional brain volumes were compared amongst the mouse lemur and several other mammalian species where high quality volumetric MRI brain atlases were available, including rodents (mouse, rat) and primates (marmoset, macaque, and human). Unlike those based on histological atlases, measures from MRI atlases indicated similar cortical to cerebral volume indices in all primates, including in mouse lemurs, and lower values in mice. On the other hand, white matter to cerebral volume index increased from rodents to small primates (mouse lemurs and marmosets) to macaque, reaching their highest values in humans.
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Atlas como Asunto , Encéfalo/anatomía & histología , Cheirogaleidae/anatomía & histología , Imagenología Tridimensional/métodos , Envejecimiento , Anatomía Comparada , Animales , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética , MasculinoRESUMEN
Astrocyte reactivity is a hallmark of neurodegenerative diseases (ND), but its effects on disease outcomes remain highly debated. Elucidation of the signaling cascades inducing reactivity in astrocytes during ND would help characterize the function of these cells and identify novel molecular targets to modulate disease progression. The Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is associated with reactive astrocytes in models of acute injury, but it is unknown whether this pathway is directly responsible for astrocyte reactivity in progressive pathological conditions such as ND. In this study, we examined whether the JAK/STAT3 pathway promotes astrocyte reactivity in several animal models of ND. The JAK/STAT3 pathway was activated in reactive astrocytes in two transgenic mouse models of Alzheimer's disease and in a mouse and a nonhuman primate lentiviral vector-based model of Huntington's disease (HD). To determine whether this cascade was instrumental for astrocyte reactivity, we used a lentiviral vector that specifically targets astrocytes in vivo to overexpress the endogenous inhibitor of the JAK/STAT3 pathway [suppressor of cytokine signaling 3 (SOCS3)]. SOCS3 significantly inhibited this pathway in astrocytes, prevented astrocyte reactivity, and decreased microglial activation in models of both diseases. Inhibition of the JAK/STAT3 pathway within reactive astrocytes also increased the number of huntingtin aggregates, a neuropathological hallmark of HD, but did not influence neuronal death. Our data demonstrate that the JAK/STAT3 pathway is a common mediator of astrocyte reactivity that is highly conserved between disease states, species, and brain regions. This universal signaling cascade represents a potent target to study the role of reactive astrocytes in ND.
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Enfermedad de Alzheimer/fisiopatología , Astrocitos , Enfermedad de Huntington/fisiopatología , Quinasas Janus , Factor de Transcripción STAT3 , Transducción de Señal , Enfermedad de Alzheimer/patología , Animales , Complejo IV de Transporte de Electrones/metabolismo , Humanos , Enfermedad de Huntington/patología , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , FN-kappa B/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genéticaRESUMEN
Abnormalities in neuronal cholesterol homeostasis have been suspected or observed in several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, it has not been demonstrated whether an increased abundance of cholesterol in neurons in vivo contributes to neurodegeneration. To address this issue, we used RNA interference methodology to inhibit the expression of cholesterol 24-hydroxylase, encoded by the Cyp46a1 gene, in the hippocampus of normal mice. Cholesterol 24-hydroxylase controls cholesterol efflux from the brain and thereby plays a major role in regulating brain cholesterol homeostasis. We used an adeno-associated virus vector encoding short hairpin RNA directed against the mouse Cyp46a1 mRNA to decrease the expression of the Cyp46a1 gene in hippocampal neurons of normal mice. This increased the cholesterol concentration in neurons, followed by cognitive deficits and hippocampal atrophy due to apoptotic neuronal death. Prior to neuronal death, the recruitment of the amyloid protein precursor to lipid rafts was enhanced leading to the production of ß-C-terminal fragment and amyloid-ß peptides. Abnormal phosphorylation of tau and endoplasmic reticulum stress were also observed. In the APP23 mouse model of Alzheimer's disease, the abundance of amyloid-ß peptides increased following inhibition of Cyp46a1 expression, and neuronal death was more widespread than in normal mice. Altogether, these results suggest that increased amounts of neuronal cholesterol within the brain may contribute to inducing and/or aggravating Alzheimer's disease.
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Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Colesterol/metabolismo , Inhibidores Enzimáticos/farmacología , Esteroide Hidroxilasas/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Colesterol 24-Hidroxilasa , Femenino , Homeostasis/fisiología , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/metabolismoRESUMEN
Decreased brain content of DHA, the most abundant long-chain n-3 polyunsaturated fatty acid (n-3 LCPUFA) in the brain, is accompanied by severe neurosensorial impairments linked to impaired neurotransmission and impaired brain glucose utilization. In the present study, we hypothesized that increasing n-3 LCPUFA intake at an early age may help to prevent or correct the glucose hypometabolism observed during aging and age-related cognitive decline. The effects of 12 months' supplementation with n-3 LCPUFA on brain glucose utilization assessed by positron emission tomography was tested in young adult mouse lemurs (Microcebus murinus). Cognitive function was tested in parallel in the same animals. Lemurs supplemented with n-3 LCPUFA had higher brain glucose uptake and cerebral metabolic rate of glucose compared with controls in all brain regions. The n-3 LCPUFA-supplemented animals also had higher exploratory activity in an open-field task and lower evidence of anxiety in the Barnes maze. Our results demonstrate for the first time in a nonhuman primate that n-3 LCPUFA supplementation increases brain glucose uptake and metabolism and concomitantly reduces anxiety.
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Ansiedad/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cheirogaleidae , Ácidos Grasos Omega-3/farmacología , Aceites de Pescado/química , Glucosa/metabolismo , Animales , Ansiedad/metabolismo , Ansiedad/fisiopatología , Metabolismo Basal/efectos de los fármacos , Transporte Biológico/efectos de los fármacos , Encéfalo/fisiopatología , Suplementos Dietéticos , Conducta Exploratoria/efectos de los fármacos , Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-3/uso terapéutico , Masculino , Memoria Espacial/efectos de los fármacosRESUMEN
Alzheimer's disease causes severe cognitive alterations in humans and is associated with two main pathologic processes: the ß-amyloid and tau pathologies. Imaging biomarkers can reveal the natural history of the disease and show an alteration of glucose metabolism and an evolving cerebral atrophy process. The discovery of new therapies against this disease relies on early stages of drug development that can be evaluated precisely only in animals. Our review focuses on transgenic mouse models of amyloidosis and on the mouse lemur primate model. Biomarkers in these animals may reveal endophenotypes that can be compared to human endophenotypes and help rationalizing decision-making during the development of new therapies. Animal models can also help to validate new hypotheses on disease mechanisms. We focus here on the protein misfolding hypothesis of Alzheimer as it will probably modulate our vision of the disease in forthcoming years. This hypothesis suggests that native Aß peptides become toxic when their conformation in alpha helices evolves into a beta-sheet conformation and also suggests that misfolded proteins can transmit their misfolded conformation to normal proteins.
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Enfermedad de Alzheimer/terapia , Investigación Biomédica Traslacional , Enfermedad de Alzheimer/metabolismo , Animales , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , HumanosRESUMEN
Amyloid plaques are one of the major microscopic lesions that characterize Alzheimer's disease. Current approaches to detect amyloid plaques by using magnetic resonance imaging (MRI) contrast agents require invasive procedures to penetrate the blood-brain barrier (BBB) and to deliver the contrast agent into the vicinity of amyloid plaques. Here we have developed a new protocol (US-Gd-staining) that enables the detection of amyloid plaques in the brain of an APP/PS1 transgenic mouse model of amyloidosis after intra-venous injection of a non-targeted, clinically approved MRI contrast agent (Gd-DOTA, Dotarem®) by transiently opening the BBB with unfocused ultrasound (1 MHz) and clinically approved microbubbles (Sonovue®, Bracco). This US-Gd-staining protocol can detect amyloid plaques with a short imaging time (32 min) and high in-plane resolution (29 µm). The sensitivity and resolution obtained is at least equal to that provided by MRI protocols using intra-cerebro-ventricular injection of contrast agents, a reference method used to penetrate the BBB. To our knowledge this is the first study to demonstrate the ability of MR imaging to detect amyloid plaques by using a peripheral intra-venous injection of a clinically approved NMR contrast agent.
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Barrera Hematoencefálica/metabolismo , Compuestos Heterocíclicos/farmacocinética , Imagen por Resonancia Magnética/métodos , Compuestos Organometálicos/farmacocinética , Placa Amiloide/metabolismo , Placa Amiloide/patología , Sonicación/métodos , Animales , Barrera Hematoencefálica/efectos de la radiación , Encéfalo/metabolismo , Encéfalo/patología , Medios de Contraste/farmacocinética , Aumento de la Imagen/métodos , Ratones , Ratones Transgénicos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Coloración y EtiquetadoRESUMEN
Solid lipid nanoparticles (SLNs) have recently emerged as nontoxic, versatile alternatives to traditional carriers (liposomes, polymeric nanoparticles) for drug delivery. Because SLNs are composed of a solid lipid core, they offer significant protection against chemical degradation of their drug cargo and offer the potential for controlled release. SLNs also hold promise for use as targeted agents and multimodal imaging agents. Here we report the synthesis and characterization of SLNs loaded with gadolinium (1,4,7,10-tetraazacyclododecane)-1,4,7,10-tetraacetate (Gd-DOTA) in order to produce a new category of stable T1-weighted (T1w) magnetic resonance imaging (MRI) contrast agents. Systematically varying components in the SLN synthesis, we demonstrated an increase in Gd-DOTA incorporation and an increase in longitudinal relaxivity (r1) through optimizing the amount of surfactant (Span 80) in the "oil" phase. These highly monodisperse SLNs confirm stable loading of Gd-DOTA and a stable size distribution (â¼150 nm) over time in aqueous solution. Relaxivity measurements (1.4T, 37 °C) demonstrate that the r1 of Gd-DOTA does not strongly decrease following encapsulation in SLNs, demonstrating an advantage over liposomes. These Gd-loaded SLNs demonstrate enhanced contrast in vivo at 7T using T1w MRI and in the future can be loaded with other cargo (hydrophilic or hydrophobic) to enable functionality with other imaging modalities such as optical or positron emission tomography.
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Medios de Contraste/administración & dosificación , Compuestos Heterocíclicos/administración & dosificación , Lípidos/química , Imagen por Resonancia Magnética/métodos , Nanopartículas/química , Compuestos Organometálicos/administración & dosificación , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Medios de Contraste/toxicidad , Compuestos Heterocíclicos/toxicidad , Lípidos/toxicidad , Ratones , Nanopartículas/toxicidad , Compuestos Organometálicos/toxicidadRESUMEN
Non-human primates are a critical species for the identification of key biological mechanisms in normal and pathological aging. One of these primates, the mouse lemur, has been widely studied as a model of cerebral aging or Alzheimer's disease. The amplitude of low-frequency fluctuations of blood oxygenation level-dependent (BOLD) can be measured with functional MRI. Within specific frequency bands (e.g. the 0.01-0.1 Hz), these amplitudes were proposed to indirectly reflect neuronal activity as well as glucose metabolism. Here, we first created whole brain maps of the mean amplitude of low frequency fluctuations (mALFF) in young mouse lemurs (mean ± SD: 2.1 ± 0.8 years). Then, we extracted mALFF in old lemurs (mean ± SD: 8.8 ± 1.1 years) to identify age-related changes. A high level of mALFF was detected in the temporal cortex (Brodmann area 20), somatosensory areas (Brodmann area 5), insula (Brodmann areas 13-6) and the parietal cortex (Brodmann area 7) of healthy young mouse lemurs. Aging was associated with alterations of mALFF in somatosensory areas (Brodmann area 5) and the parietal cortex (Brodmann area 7).
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Enfermedad de Alzheimer , Cheirogaleidae , Lemur , Lemuridae , Corteza Sensoriomotora , Strepsirhini , Animales , Cheirogaleidae/fisiología , Imagen por Resonancia Magnética , Encéfalo/patología , Envejecimiento , Enfermedad de Alzheimer/patologíaRESUMEN
Circulating microRNAs (miRNAs) have aroused a lot of interest as reliable blood diagnostic biomarkers of Alzheimer's disease (AD). Here, we investigated the panel of expressed blood miRNAs in response to aggregated Aß1-42 peptides infused in the hippocampus of adult rats to mimic events of the early onset of non-familial AD disorder. Aß1-42 peptides in the hippocampus led to cognitive impairments associated with an astrogliosis and downregulation of circulating miRNA-146a-5p, -29a-3p, -29c-3p, -125b-5p, and-191-5p. We established the kinetics of expression of selected miRNAs and found differences with those detected in the APPswe/PS1dE9 transgenic mouse model. Of note, miRNA-146a-5p was exclusively dysregulated in the Aß-induced AD model. The treatment of primary astrocytes with Aß1-42 peptides led to miRNA-146a-5p upregulation though the activation of the NF-κB signaling pathway, which in turn downregulated IRAK-1 but not TRAF-6 expression. As a consequence, no induction of IL-1ß, IL-6, or TNF-α was detected. Astrocytes treated with a miRNA-146-5p inhibitor rescued IRAK-1 and changed TRAF-6 steady-state levels that correlated with the induction of IL-6, IL-1ß, and CXCL1 production, indicating that miRNA-146a-5p operates anti-inflammatory functions through a NF-κB pathway negative feedback loop. Overall, we report a panel of circulating miRNAs that correlated with Aß1-42 peptides' presence in the hippocampus and provide mechanistic insights into miRNA-146a-5p biological function in the development of the early stage of sporadic AD.
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Enfermedad de Alzheimer , MicroARNs , Animales , Ratones , Ratas , Enfermedad de Alzheimer/metabolismo , Antiinflamatorios/metabolismo , Astrocitos/metabolismo , Interleucina-6/metabolismo , MicroARNs/metabolismo , FN-kappa B/metabolismoRESUMEN
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.
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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 EnfermedadRESUMEN
Manganese-enhanced MRI (MEMRI) is a powerful technique for the in vivo monitoring of brain function in animals. Manganese enters into cells through calcium channels, i.e., voltage-gated calcium channels and activated glutamate receptors (e.g., N-methyl-D-aspartate receptors). N-methyl-D-aspartate receptors are activated both in normal physiological and pathophysiological conditions. Consistent with these mechanisms, we showed that in the olfactory bulb, the MEMRI signal strongly increases when excitotoxic mechanisms are induced by an administration of a N-methyl-D-aspartate receptor agonist, quinolinate. We found that the intensity of the MEMRI signal in excitotoxic conditions is similar to the odor-evoked signal in normal physiological conditions. Finally, we showed that the dynamics of the MEMRI signal are determined by the early phase of manganese in the olfactory bulb. Overall, these data show that, in addition to physiological studies, MEMRI can be used as an in vivo method to follow-up the dynamics of excitotoxic events.
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Encéfalo/efectos de los fármacos , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Manganeso/toxicidad , Olfato/fisiología , Animales , Medios de Contraste/toxicidad , Aumento de la Imagen/métodos , Masculino , Odorantes , Ácido Quinolínico/farmacología , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Olfato/efectos de los fármacosRESUMEN
Alzheimer's disease (AD) is characterized by intracerebral accumulations of extracellular amyloid-ß (Aß) plaques and intracellular tau pathology that spread in the brain. Three types of tau lesions occur in the form of neuropil threads, neurofibrillary tangles, and neuritic plaques i.e. tau aggregates within neurites surrounding Aß deposits. The cascade of events linking these lesions and synaptic or memory impairments are still debated. Intracerebral infusion of human AD brain extracts in Aß plaque-bearing mice that do not overexpress pathological tau proteins induces tau pathologies following heterotopic seeding of mouse tau protein. There is however little information regarding the downstream events including synaptic or cognitive repercussions of tau pathology induction in these models. In the present study, human AD brain extracts (ADbe) and control-brain extracts (Ctrlbe) were infused into the hippocampus of Aß plaque-bearing APPswe/PS1dE9 mice. Memory, synaptic density, as well as Aß plaque and tau aggregate loads, microgliosis, astrogliosis at the inoculation site and in connected regions (perirhinal/entorhinal cortex) were evaluated 4 and 8 months post-inoculation. ADbe inoculation produced the following effects: (i) memory deficit; (ii) increased Aß plaque deposition in proximity to the inoculation site; (iii) tau pathology induction; (iv) appearance of neuropil threads and neurofibrillary tangles next to the inoculation site with a spreading to connected regions. Neuritic plaque pathology was detected in both ADbe- and Ctrlbe-inoculated animals but ADbe inoculation increased the severity close to and at distance of the inoculation site. (v) Finally, ADbe inoculation reduced synaptic density in the vicinity to the inoculation site and in connected regions as the perirhinal/entorhinal cortex. Synaptic impairments were correlated with increased severity of neuritic plaques but not to other tau lesions or Aß lesions, suggesting that neuritic plaques are a culprit for synaptic loss. Synaptic density was also associated with microglial load.
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Enfermedad de Alzheimer , Placa Amiloide , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/patología , Humanos , Ratones , Ovillos Neurofibrilares/patología , Placa Amiloide/patología , Proteínas tau/metabolismoRESUMEN
The human default mode network (DMN) is engaged at rest and in cognitive states such as self-directed thoughts. Interconnected homologous cortical areas in primates constitute a network considered as the equivalent. Here, based on a cross-species comparison of the DMN between humans and non-hominoid primates (macaques, marmosets, and mouse lemurs), we report major dissimilarities in connectivity profiles. Most importantly, the medial prefrontal cortex (mPFC) of non-hominoid primates is poorly engaged with the posterior cingulate cortex (PCC), though strong correlated activity between the human PCC and the mPFC is a key feature of the human DMN. Instead, a fronto-temporal resting-state network involving the mPFC was detected consistently across non-hominoid primate species. These common functional features shared between non-hominoid primates but not with humans suggest a substantial gap in the organization of the primate's DMN and its associated cognitive functions.
Asunto(s)
Mapeo Encefálico , Encéfalo , Animales , Callithrix , Red en Modo Predeterminado , Imagen por Resonancia Magnética , Vías NerviosasRESUMEN
The cerebral metabolic rate of oxygen consumption (CMRO2) is a key metric to investigate the mechanisms involved in neurodegeneration in animal models and evaluate potential new therapies. CMRO2 can be measured by direct 17O magnetic resonance imaging (17O-MRI) of H217O signal changes during inhalation of 17O-labeled oxygen gas. In this study, we built a simple gas distribution system and used 3D zero echo time (ZTE-)MRI at 11.7 T to measure CMRO2 in the APPswe/PS1dE9 mouse model of amyloidosis. We found that CMRO2 was significantly lower in the APPswe/PS1dE9 brain than in wild-type at 12-14 months. We also estimated cerebral blood flow (CBF) from the post-inhalation washout curve and found no difference between groups. These results suggest that the lower CMRO2 observed in APPswe/PS1dE9 is likely due to metabolism impairment rather than to reduced blood flow. Analysis of the 17O-MRI data using different quantification models (linear and 3-phase model) showed that the choice of the model does not affect group comparison results. However, the simplified linear model significantly underestimated the absolute CMRO2 values compared to a 3-phase model. This may become of importance when combining several metabolic fluxes measurements to study neuro-metabolic coupling.
RESUMEN
Amyloid-ß (Aß) pathology transmission has been described in patients following iatrogenic exposure to compounds contaminated with Aß proteins. It can induce cerebral Aß angiopathy resulting in brain hemorrhages and devastating clinical impacts. Iatrogenic transmission of tau pathology is also suspected but not experimentally proven. In both scenarios, lesions were detected several decades after the putatively triggering medico-surgical act. There is however little information regarding the cognitive repercussions in individuals who do not develop cerebral hemorrhages. In the current study, we inoculated the posterior cingulate cortex and underlying corpus callosum of young adult primates (Microcebus murinus) with either Alzheimer's disease or control brain extracts. This led to widespread Aß and tau pathologies in all of the Alzheimer-inoculated animals following a 21-month-long incubation period (n = 12) whereas none of the control brain extract-inoculated animals developed such lesions (n = 6). Aß deposition affected almost all cortical regions. Tau pathology was also detected in Aß-deposit-free regions distant from the inoculation sites (e.g. in the entorhinal cortex), while some regions adjacent, but not connected, to the inoculation sites were spared (e.g. the occipital cortex). Alzheimer-inoculated animals developed cognitive deficits and cerebral atrophy compared to controls. These pathologies were induced using two different batches of Alzheimer brain extracts. This is the first experimental demonstration that tau can be transmitted by human brain extracts inoculations in a primate. We also showed for the first time that the transmission of widespread Aß and tau pathologies can be associated with cognitive decline. Our results thus reinforce the need to organize a systematic monitoring of individuals who underwent procedures associated with a risk of Aß and tau iatrogenic transmission. They also provide support for Alzheimer brain-inoculated primates as relevant models of Alzheimer pathology.