RESUMEN
Proteins of the major histocompatibility complex class I (MHC I), predominantly known for antigen presentation in the immune system, have recently been shown to be necessary for developmental neural refinement and adult synaptic plasticity. However, their roles in nonneuronal cell populations in the brain remain largely unexplored. Here, we identify classical MHC I molecule H2-Kb as a negative regulator of proliferation in neural stem and progenitor cells (NSPCs). Using genetic knockout mouse models and in vivo viral-mediated RNA interference (RNAi) and overexpression, we delineate a role for H2-Kb in negatively regulating NSPC proliferation and adult hippocampal neurogenesis. Transcriptomic analysis of H2-Kb knockout NSPCs, in combination with in vitro RNAi, overexpression, and pharmacological approaches, further revealed that H2-Kb inhibits cell proliferation by dampening signaling pathways downstream of fibroblast growth factor receptor 1 (Fgfr1). These findings identify H2-Kb as a critical regulator of cell proliferation through the modulation of growth factor signaling.
Asunto(s)
Antígenos de Histocompatibilidad Clase I/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal , Envejecimiento/metabolismo , Animales , Ciclo Celular , Proliferación Celular , Hipocampo/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , NeurogénesisRESUMEN
Seminal studies using post-mortem brains of patients with Alzheimer's disease evidenced aberrant insulin-like growth factor 1 receptor (IGF1R) signalling. Addressing causality, work in animal models recently demonstrated that long-term suppression of IGF1R signalling alleviates Alzheimer's disease progression and promotes neuroprotection. However, the underlying mechanisms remain largely elusive. Here, we showed that genetically ablating IGF1R in neurons of the ageing brain efficiently protects from neuroinflammation, anxiety and memory impairments induced by intracerebroventricular injection of amyloid-ß oligomers. In our mutant mice, the suppression of IGF1R signalling also invariably led to small neuronal soma size, indicative of profound changes in cellular homeodynamics. To gain insight into transcriptional signatures leading to Alzheimer's disease-relevant neuronal defence, we performed genome-wide microarray analysis on laser-dissected hippocampal CA1 after neuronal IGF1R knockout, in the presence or absence of APP/PS1 transgenes. Functional analysis comparing neurons in early-stage Alzheimer's disease with IGF1R knockout neurons revealed strongly convergent transcriptomic signatures, notably involving neurite growth, cytoskeleton organization, cellular stress response and neurotransmission. Moreover, in Alzheimer's disease neurons, a high proportion of genes responding to Alzheimer's disease showed a reversed differential expression when IGF1R was deleted. One of the genes consistently highlighted in genome-wide comparison was the neurofilament medium polypeptide Nefm. We found that NEFM accumulated in hippocampus in the presence of amyloid pathology, and decreased to control levels under IGF1R deletion, suggesting that reorganized cytoskeleton likely plays a role in neuroprotection. These findings demonstrated that significant resistance of the brain to amyloid-ß can be achieved lifelong by suppressing neuronal IGF1R and identified IGF-dependent molecular pathways that coordinate an intrinsic program for neuroprotection against proteotoxicity. Our data also indicate that neuronal defences against Alzheimer's disease rely on an endogenous gene expression profile similar to the neuroprotective response activated by genetic disruption of IGF1R signalling. This study highlights neuronal IGF1R signalling as a relevant target for developing Alzheimer's disease prevention strategies.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Región CA1 Hipocampal/metabolismo , Fármacos Neuroprotectores/metabolismo , Receptor IGF Tipo 1/deficiencia , Receptor IGF Tipo 1/genética , Transcriptoma , Envejecimiento/metabolismo , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/administración & dosificación , Animales , Ansiedad/inducido químicamente , Ansiedad/complicaciones , Ansiedad/prevención & control , Encefalitis/inducido químicamente , Encefalitis/complicaciones , Encefalitis/prevención & control , Femenino , Infusiones Intraventriculares , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/prevención & control , Ratones , Ratones Noqueados , Ratones Transgénicos , Neuronas/metabolismoRESUMEN
Alzheimer's disease (AD) is a frequent and irreversible age-related neurodegeneration without efficient treatment. Experimental AD in mice responds positively to decreased insulin-like growth factor I (IGF-I) signaling, a pathway also implicated in aging. Here we aimed to protect the aging brain from devastating amyloid pathology by making specifically adult neurons resistant to IGF signaling. To achieve that, we knocked out neuronal IGF-1R during adulthood in APP/PS1 mice. We found that mutants exhibited improved spatial memory and reduced anxiety. Mutant brains displayed fewer amyloid plaques, less amyloid-ß (Aß), and diminished neuroinflammation. Surprisingly, adult neurons undergoing IGF-1R knock-out reduced their apical soma and developed leaner dendrites, indicative of remarkable structural plasticity entailing condensed forebrain neuroarchitecture. Neurons lacking IGF-1R in AD showed less accumulation of Aß-containing autophagic vacuoles. At the same time, plasma Aß levels were increased. Our data indicate that neuronal IGF-1R ablation, via preserved autophagic compartment and enhanced systemic elimination, offers lifelong protection from AD pathology by clearing toxic Aß. Neuronal IGF-1R, and possibly other cell size-controlling pathways are promising targets for AD treatment. SIGNIFICANCE STATEMENT: We found compelling evidence in vivo that Alzheimer's disease (AD) progression is significantly delayed when insulin-like growth factor (IGF) signaling is blocked in adult neurons. To show that, we built a novel mouse model, combining inducible neuron-specific IGF-1R knock-out with AD transgenics. Analysis of the experimental AD phenotype revealed less abundant amyloid-ß (Aß) peptides, fewer plaques, and diminished neuroinflammation in mutants with inactivated IGF signaling, together with clearly preserved behavioral and memory performances. We present for the first time evidence that IGF signaling has profound effects on neuronal proteostasis and maintenance of cell morphology in vivo. Our results indicate in a model highly pertinent to translational research that neuronal IGF resistance may represent a pathophysiologically relevant mechanism of the brain for preventing Aß accumulation.
Asunto(s)
Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neuronas/metabolismo , Neuronas/patología , Animales , Conducta Animal , Tamaño de la Célula , Células Cultivadas , Regulación hacia Abajo , Femenino , Masculino , Aprendizaje por Laberinto , Tasa de Depuración Metabólica , Ratones , Ratones Noqueados , Ratones Transgénicos , Prosencéfalo/metabolismo , Prosencéfalo/patología , Receptor IGF Tipo 1/genética , Transducción de SeñalRESUMEN
DNA methylation has emerged as a critical modulator of neuronal plasticity and cognitive function. Notwithstanding, the role of enzymes that demethylate DNA remain to be fully explored. Here, we report that loss of ten-eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), in adult neurons enhances cognitive function. In the adult mouse hippocampus, we detected an enrichment of Tet2 in neurons. Viral-mediated neuronal overexpression and RNA interference of Tet2 altered dendritic complexity and synaptic-plasticity-related gene expression in vitro. Overexpression of neuronal Tet2 in adult hippocampus, and loss of Tet2 in adult glutamatergic neurons, resulted in differential hydroxymethylation associated with genes involved in synaptic transmission. Functionally, overexpression of neuronal Tet2 impaired hippocampal-dependent memory, while loss of neuronal Tet2 enhanced memory. Ultimately, these data identify neuronal Tet2 as a molecular target to boost cognitive function.
Asunto(s)
Dioxigenasas , Proteínas Proto-Oncogénicas , Animales , Ratones , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Unión al ADN/metabolismo , 5-Metilcitosina/metabolismo , Dioxigenasas/genética , Metilación de ADN/genética , Cognición , Neuronas/metabolismo , Hipocampo/metabolismoRESUMEN
Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.
Asunto(s)
Envejecimiento/sangre , Encéfalo/fisiología , Cognición/fisiología , Hígado/enzimología , Neurogénesis , Fosfolipasa D/sangre , Condicionamiento Físico Animal , Animales , Circulación Sanguínea , Encéfalo/irrigación sanguínea , Disfunción Cognitiva/sangre , Disfunción Cognitiva/fisiopatología , Glicosilfosfatidilinositoles/metabolismo , Ratones , Fosfolipasa D/metabolismo , Regeneración , Transducción de SeñalRESUMEN
Restoring adult stem cell function provides an exciting approach for rejuvenating the aging brain. However, molecular mechanisms mediating neurogenic rejuvenation remain elusive. Here we report that the enzyme ten eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes the production of 5-hydroxymethylcytosine (5hmC), rescues age-related decline in adult neurogenesis and enhances cognition in mice. We detected a decrease in Tet2 expression and 5hmC levels in the aged hippocampus associated with adult neurogenesis. Mimicking an aged condition in young adults by abrogating Tet2 expression within the hippocampal neurogenic niche, or adult neural stem cells, decreased neurogenesis and impaired learning and memory. In a heterochronic parabiosis rejuvenation model, hippocampal Tet2 expression was restored. Overexpressing Tet2 in the hippocampal neurogenic niche of mature adults increased 5hmC associated with neurogenic processes, offset the precipitous age-related decline in neurogenesis, and enhanced learning and memory. Our data identify Tet2 as a key molecular mediator of neurogenic rejuvenation.
Asunto(s)
Envejecimiento/patología , Encéfalo/fisiopatología , Cognición , Proteínas de Unión al ADN/metabolismo , Regeneración Nerviosa , Proteínas Proto-Oncogénicas/metabolismo , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Animales , Giro Dentado/metabolismo , Giro Dentado/patología , Giro Dentado/fisiopatología , Dioxigenasas , Masculino , Ratones Endogámicos C57BL , Modelos Animales , Células-Madre Neurales/metabolismo , Neurogénesis , ParabiosisRESUMEN
Identifying factors driving neural stem cell dysfunction in age-related neurodegenerative diseases remains critical for the development of potential regenerative therapies. Now in Cell Stem Cell,Hamilton et al. (2015) find that lipid accumulation observed during early stages of Alzheimer's disease impairs neural stem cell activity in the adult brain.
Asunto(s)
Metabolismo de los Lípidos , Células-Madre Neurales , Prosencéfalo/metabolismo , AnimalesRESUMEN
Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify ß2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.
Asunto(s)
Envejecimiento , Cognición , Neurogénesis , Microglobulina beta-2/fisiología , Transportador de Casetes de Unión a ATP, Subfamilia B, Miembro 2 , Transportadoras de Casetes de Unión a ATP/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Humanos , Complejo Mayor de Histocompatibilidad/fisiología , Ratones , Ratones Endogámicos C57BL , Persona de Mediana EdadRESUMEN
Growth hormone (GH) and insulin-like growth factor (IGF) signaling regulates lifespan in mice. The modulating effects of genetic background gained much attention because it was shown that life-prolonging effects in Snell dwarf and GH receptor knockout vary between mouse strains. We previously reported that heterozygous IGF-1R inactivation (IGF-1R(+/-) ) extends lifespan in female mice on 129/SvPas background, but it remained unclear whether this mutation produces a similar effect in other genetic backgrounds and which molecules possibly modify this effect. Here, we measured the life-prolonging effect of IGF-1R(+/-) mutation in C57BL/6J background and investigated the role of insulin/IGF signaling molecules in strain-dependent differences. We found significant lifespan extension in female IGF-1R(+/-) mutants on C57BL/6J background, but the effect was smaller than in 129/SvPas, suggesting strain-specific penetrance of longevity phenotypes. Comparing GH/IGF pathways between wild-type 129/SvPas and C57BL/6J mice, we found that circulating IGF-I and activation of IGF-1R, IRS-1, and IRS-2 were markedly elevated in 129/SvPas, while activation of IGF pathways was constitutively low in spontaneously long-lived C57BL/6J mice. Importantly, we demonstrated that loss of one IGF-1R allele diminished the level of activated IGF-1R and IRS more profoundly and triggered stronger endocrine feedback in 129/SvPas background than in C57BL/6J. We also revealed that acute oxidative stress entails robust IGF-1R pathway activation, which could account for the fact that IGF-1R(+/-) stress resistance phenotypes are fully penetrant in both backgrounds. Together, these results provide a possible explanation why IGF-1R(+/-) was less efficient in extending lifespan in C57BL/6J compared with 129/SvPas.
Asunto(s)
Longevidad/genética , Mutación/genética , Receptor IGF Tipo 1/genética , Animales , Tamaño Corporal/efectos de los fármacos , Femenino , Glucosa/metabolismo , Heterocigoto , Proteínas Sustrato del Receptor de Insulina/metabolismo , Longevidad/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Estrés Oxidativo/efectos de los fármacos , Paraquat/toxicidad , Fosfotirosina/metabolismo , Transducción de Señal/efectos de los fármacos , Somatomedinas/metabolismoRESUMEN
BACKGROUND: Central nervous system infection is a daily concern in neurointensive care; however, diagnosis remains difficult because classical criteria based on cerebrospinal fluid (CSF) analysis are difficult to interpret in post-trauma or neurosurgery patients after recent bleeding. A rapid, specific, sensitive test to diagnose CSF infection would help streamline therapeutic decisions in clinical practice and limit the risk of multiresistant bacteria. We hypothesized that polymorphonuclear neutrophil (PMN) phenotype and radical oxygen species (ROS) production in CSF may be specific to the presence of infection. METHODS: This study included 30 patients with suspected CSF infection with ventricular hemorrhage requiring external ventricular drainage, and 13 patients after trauma or surgery. Criteria for evaluating CSF infection included positive culture and > 100 leukocytes/mm3. Analysis of PMN phenotype was performed using flow cytometry (CD16, CD11b, and CD62L). ROS production was analyzed through luminometry (luminol). RESULTS: Infected CSF exhibited higher production of ROS compared with noninfected CSF. PMNs in CSF exhibited low CD16 and high annexin V expression, suggesting apoptosis. CONCLUSIONS: Measurement of ROS production may discriminate infected from noninfected CSF. This simple test would be easy to employ in clinical practice to improve CSF infection management.
RESUMEN
The role of the somatotropic hormone axis in mammalian longevity has been studied in diverse experimental models in vivo. This endocrine axis allows regulation of lifespan via metabolism modifications and oxidative stress defense mechanisms. Signaling can be altered at ligand, receptor or signal transduction molecule level through mutagenesis. Mutant mouse models affecting pituitary differentiation factors Prop-1 or Pit1, cognate receptors of GH, IGF or insulin, or receptor substrates IRS-1 or IRS-2 showed that regulation of the somatotropic endocrine axis is pivotal for maintaining an equilibrium between growth, metabolism, oxidative stress defense and longevity. Brain-specific gene inactivation of IGF-1R and IRS-2 resulted in similarly long-lived phenotypes indicating that control of longevity is possible by selectively targeting the brain. In addition to genetic modification, lifespan can be efficiently manipulated in mice by altering the environment, for instance by modifying caloric intake, or pharmacologically, as has been shown in a recent study about the effects of rapamycin on lifespan. Moreover, recent studies of the human genetics of aging revealed that mutations of IGF-1R and variants of FoxO3a are more frequent in certain centenarian cohorts. This suggested that these results are in principle transposable to humans.