RESUMO
Transient soluble oligomers of amyloid-ß (Aß) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer's disease (AD). Synthetic cyclic D,L-α-peptides (e.g., 1) self-assemble into cross ß-sheet nanotubes, react with early Aß species (1-3 mers), and inhibit Aß aggregation and toxicity in stoichiometric concentrations, in vitro. Employing a semicarbazide as an aza-glycine residue with an extra hydrogen-bond donor to tune nanotube assembly and amyloid engagement, [azaGly6]-1 inhibited Aß aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly6]-1 and Aß42 residues F19 and F20, which are pivotal for early dimerization and aggregation. In an AD mouse model, brain positron emission tomography (PET) imaging using stable 64Cu-labeled (aza)peptide tracers gave unprecedented early amyloid detection in 44-d presymptomatic animals. No tracer accumulation was detected in the cortex and hippocampus of 44-d-old 5xFAD mice; instead, intense PET signal was observed in the thalamus, from where Aß oligomers may spread to other brain parts with disease progression. Compared with standard 11C-labeled Pittsburgh compound-B (11C-PIB), which binds specifically fibrillar Aß plaques, 64Cu-labeled (aza)peptide gave superior contrast and uptake in young mouse brain correlating with Aß oligomer levels. Effectively crossing the blood-brain barrier (BBB), peptide 1 and [azaGly6]-1 reduced Aß oligomer levels, prolonged lifespan of AD transgenic Caenorhabditis elegans, and abated memory and behavioral deficits in nematode and murine AD models. Cyclic (aza)peptides offer novel promise for early AD diagnosis and therapy.
Assuntos
Doença de Alzheimer , Amiloidose , Animais , Camundongos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Diagnóstico Precoce , Peptídeos beta-Amiloides , Placa Amiloide , Proteínas AmiloidogênicasRESUMO
Williams syndrome (WS) is a genetic neurodevelopmental disorder caused by a heterozygous microdeletion, characterized by hypersociability and unique neurocognitive abnormalities. Of the deleted genes, GTF2I has been linked to hypersociability in WS. We have recently shown that Gtf2i deletion from forebrain excitatory neurons, referred to as Gtf2i conditional knockout (cKO) mice leads to multi-faceted myelination deficits associated with the social behaviors affected in WS. These deficits were potentially mediated also by microglia, as they present a close relationship with oligodendrocytes. To study the impact of altered myelination, we characterized these mice in terms of microglia over the course of development. In postnatal day 30 (P30) Gtf2i cKO mice, cortical microglia displayed a more ramified state, as compared with wild type (controls). However, postnatal day 4 (P4) microglia exhibited high proliferation rates and an elevated activation state, demonstrating altered properties related to activation and inflammation in Gtf2i cKO mice compared with control. Intriguingly, P4 Gtf2i cKO-derived microglial cells exhibited significantly elevated myelin phagocytosis in vitro compared to control mice. Lastly, systemic injection of clemastine to P4 Gtf2i cKO and control mice until P30, led to a significant interaction between genotypes and treatments on the expression levels of the phagocytic marker CD68, and a significant reduction of the macrophage/microglial marker Iba1 transcript levels in the cortex of the Gtf2i cKO treated mice. Our data thus implicate microglia as important players in WS, and that early postnatal manipulation of microglia might be beneficial in treating inflammatory and myelin-related pathologies.
Assuntos
Fatores de Transcrição TFIII , Fatores de Transcrição TFII , Síndrome de Williams , Camundongos , Animais , Microglia , Síndrome de Williams/genética , Neurônios/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição TFIII/metabolismo , Fatores de Transcrição TFII/genética , Fatores de Transcrição TFII/metabolismoRESUMO
Alzheimer's disease (AD) is linked to toxic Aß plaques in the brain and activation of innate responses. Recent findings however suggest that the disease may also depend on the adaptive immunity, as B cells exacerbate and CD8+ T cells limit AD-like pathology in mouse models of amyloidosis. Here, by artificially blocking or augmenting CD8+ T cells in the brain of 5xFAD mice, we provide evidence that AD-like pathology is promoted by pathogenic, proinflammatory cytokines and exhaustion markers expressing CXCR6+ CD39+CD73+/- CD8+ TRM-like cells. The CD8+ T cells appear to act by targeting disease associated microglia (DAM), as we find them in tight complexes with microglia around Aß plaques in the brain of mice and humans with AD. We also report that these CD8+ T cells are induced by B cells in the periphery, further underscoring the pathogenic importance of the adaptive immunity in AD. We propose that CD8+ T cells and B cells should be considered as therapeutic targets for control of AD, as their ablation at the onset of AD is sufficient to decrease CD8+ T cells in the brain and block the amyloidosis-linked neurodegeneration.
RESUMO
Innate immune receptors, well known mediators of response to non-self-molecules and inflammation, also act as mediators of immunity triggered by 'damage-associated molecular patterns' (DAMPs). Pathogen-associated molecular patterns (PAMPs) cause inflammation in mammals and a rapid immune response in plants, while DAMPs trigger more complex responses, including immunity, tissue maintenance and repair. DAMPs, their receptors and downstream transduction mechanisms are often conserved within a kingdom or, due to convergent evolution, are similar across the kingdoms of life. Herein, we describe the dynamics and functionality of specific extracellular DAMP classes and their receptors in immunity, inflammation and repair of tissue damage in plants and mammals.
Assuntos
Alarminas/metabolismo , Imunidade , Mamíferos/imunologia , Imunidade Vegetal , Plantas/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Animais , Espaço Extracelular , Humanos , CicatrizaçãoRESUMO
Down Syndrome (DS), the most common cause of genetic intellectual disability, is characterized by over-expression of the APP and DYRK1A genes, located on the triplicated chromosome 21. This chromosomal abnormality leads to a cognitive decline mediated by Amyloid-ß (Aß) overproduction and tau hyper-phosphorylation as early as the age of 40. In this study, we used the Ts65Dn mouse model of DS to evaluate the beneficial effect of a DNA vaccination against the Aß1-11 fragment, in ameliorating Aß-related neuropathology and rescue of cognitive and behavioral abilities. Anti-Aß1-11 vaccination induced antibody production and facilitated clearance of soluble oligomers and small extracellular inclusions of Aß from the hippocampus and cortex of Ts65Dn mice. This was correlated with reduced neurodegeneration and restoration of the homeostatic phenotype of microglial and astroglial cells. Vaccinated Ts65Dn mice performed better in spatial-learning tasks, exhibited reduced motor hyperactivity typical for this strain, and restored short-term memory abilities. Our findings support the hypothesis that DS individuals may benefit from active immunotherapy against Aß from a young age by slowing the progression of dementia.
Assuntos
Peptídeos beta-Amiloides/imunologia , Síndrome de Down/imunologia , Síndrome de Down/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Astrócitos/imunologia , Astrócitos/metabolismo , Encéfalo/metabolismo , DNA/imunologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Imunização/métodos , Masculino , Camundongos , Camundongos Transgênicos , Microglia/imunologia , Microglia/metabolismo , Fenótipo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas tau , Quinases DyrkRESUMO
Dopamine is known to differentially modulate the impact of cortical input to the striatum between the direct and indirect pathways of the basal ganglia (BG). However, the role of extrastriatal dopamine receptors (DRs) in BG information processing is less clear. To investigate the role of extrastriatal DRs, we studied their distribution and function in one of the output nuclei of the BG of the rodent, the entopeduncular nucleus (EP). qRT-PCR indicated that all DR subtypes were expressed by EP neurons, suggesting that both D1-like receptors (D1LRs) and D2-like receptors (D2LRs) were likely to affect information processing in the EP. Whole-cell recordings revealed that striatal inputs to the EP were potentiated by D1LRs whereas pallidal inputs to the EP were depressed by D2LRs. Changes to the paired-pulse ratio of inputs to the EP suggested that dopaminergic modulation of striatal inputs is mediated by postsynaptic receptors, and that of globus pallidus-evoked inputs is mediated by presynaptic receptors. We show that these changes in synaptic efficacy changed the information content of EP neuron firing. Overall, the findings suggest that the dopaminergic system affects the passage of feedforward information through the BG by modulating input divergence in the striatum and output convergence in the EP.SIGNIFICANCE STATEMENT The entopeduncular nucleus (EP), one of the basal ganglia (BG) output nuclei, is an important station in information processing in BG. However, it remains unclear how EP neurons encode information and how dopamine affects this process. This contrasts with the well established role of dopamine in the striatum, which is known to redistribute cortical input between the direct and indirect pathways. Here we show that, in symmetry with the striatum, dopamine controls the rebalancing of information flow between the two pathways in the EP. Specifically, we demonstrate that dopamine regulates EP activity by differentially modulating striatal and pallidal GABAergic inputs. These results call for a reassessment of current perspectives on BG information processing by highlighting the functional role of extrastriatal dopamine receptors.
Assuntos
Potenciais de Ação/fisiologia , Gânglios da Base/fisiologia , Núcleo Entopeduncular/fisiologia , Modelos Neurológicos , Receptores Dopaminérgicos/metabolismo , Transmissão Sináptica/fisiologia , Animais , Simulação por Computador , Dopamina , Neurônios Dopaminérgicos , Feminino , Rede Nervosa/fisiologia , Vias Neurais/fisiologia , Ratos , Ratos WistarRESUMO
MOTIVATION: Spatial learning is one of the most widely studied cognitive domains in neuroscience. The Morris water maze and the Barnes maze are the most commonly used techniques to assess spatial learning and memory in rodents. Despite the fact that these tasks are well-validated paradigms for testing spatial learning abilities, manual categorization of performance into behavioral strategies is subject to individual interpretation, and thus to bias. We have previously described an unbiased machine-learning algorithm to classify spatial strategies in the Morris water maze. RESULTS: Here, we offer a support vector machine-based, automated, Barnes-maze unbiased strategy (BUNS) classification algorithm, as well as a cognitive score scale that can be used for memory acquisition, reversal training and probe trials. The BUNS algorithm can greatly benefit Barnes maze users as it provides a standardized method of strategy classification and cognitive scoring scale, which cannot be derived from typical Barnes maze data analysis. AVAILABILITY AND IMPLEMENTATION: Freely available on the web at http://okunlab.wix.com/okunlab as a MATLAB application. CONTACT: eitan.okun@biu.ac.ilSupplementary information: Supplementary data are available at Bioinformatics online.
Assuntos
Algoritmos , Aprendizagem em Labirinto , Animais , Memória , Máquina de Vetores de SuporteRESUMO
OBJECTIVE: Epilepsy affects 60 million people worldwide. Despite the development of antiepileptic drugs, up to 35% of patients are drug refractory with uncontrollable seizures. Toll-like receptors (TLRs) are central components of the nonspecific innate inflammatory response. Because TLR3 was recently implicated in neuronal plasticity, we hypothesized that it may contribute to the development of epilepsy after status epilepticus (SE). METHODS: To test the involvement of TLR3 in epileptogenesis, we used the pilocarpine model for SE in TLR3-deficient mice and their respective wild-type controls. In this model, a single SE event leads to spontaneous recurrent seizures (SRS). Two weeks after SE, mice were implanted with wireless electroencephalography (EEG) transmitters for up to 1 month. The impact of TLR3 deficiency on SE was assessed using separate cohorts of mice regarding EEG activity, seizure progression, hippocampal microglial distribution, and expression of the proinflammatory cytokines tumor necrosis factor (TNF)α and interferon (IFN)ß. RESULTS: Our data indicate that TLR3 deficiency reduced SRS, microglial activation, and the levels of the proinflammatory cytokines TNFα and IFNß, and increased survival following SE. SIGNIFICANCE: This study reveals novel insights into the pathophysiology of epilepsy and the contribution of TLR3 to disease progression. Our results identify the TLR3 pathway as a potential future therapeutic target in SE.
Assuntos
Convulsivantes/toxicidade , Epilepsia/induzido quimicamente , Epilepsia/genética , Pilocarpina/toxicidade , Receptor 3 Toll-Like/deficiência , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia/mortalidade , Epilepsia/patologia , Hipocampo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , RNA Mensageiro/metabolismo , Estatísticas não Paramétricas , Fatores de Tempo , Receptor 3 Toll-Like/genéticaRESUMO
The assessment of spatial cognitive learning in rodents is a central approach in neuroscience, as it enables one to assess and quantify the effects of treatments and genetic manipulations from a broad perspective. Although the Morris water maze (MWM) is a well-validated paradigm for testing spatial learning abilities, manual categorization of performance in the MWM into behavioral strategies is subject to individual interpretation, and thus to biases. Here we offer a support vector machine (SVM) - based, automated, MWM unbiased strategy classification (MUST-C) algorithm, as well as a cognitive score scale. This model was examined and validated by analyzing data obtained from five MWM experiments with changing platform sizes, revealing a limitation in the spatial capacity of the hippocampus. We have further employed this algorithm to extract novel mechanistic insights on the impact of members of the Toll-like receptor pathway on cognitive spatial learning and memory. The MUST-C algorithm can greatly benefit MWM users as it provides a standardized method of strategy classification as well as a cognitive scoring scale, which cannot be derived from typical analysis of MWM data.
Assuntos
Algoritmos , Cognição/fisiologia , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Aprendizagem Espacial/fisiologia , Animais , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Percepção Espacial/fisiologia , Máquina de Vetores de Suporte , Natação/fisiologiaRESUMO
Neuroinflammation in the central nervous system is detrimental for learning and memory, as evident form epidemiological studies linking developmental defects and maternal exposure to harmful pathogens. Postnatal infections can also induce neuroinflammatory responses with long-term consequences. These inflammatory responses can lead to motor deficits and/or behavioral disabilities. Toll like receptors (TLRs) are a family of innate immune receptors best known as sensors of microbial-associated molecular patterns, and are the first responders to infection. TLR2 forms heterodimers with either TLR1 or TLR6, is activated in response to gram-positive bacterial infections, and is expressed in the brain during embryonic development. We hypothesized that early postnatal TLR2-mediated neuroinflammation would adversely affect cognitive behavior in the adult. Our data indicate that postnatal TLR2 activation affects learning and memory in adult mice in a heterodimer-dependent manner. TLR2/6 activation improved motor function and fear learning, while TLR2/1 activation impaired spatial learning and enhanced fear learning. Moreover, developmental TLR2 deficiency significantly impairs spatial learning and enhances fear learning, stressing the involvement of the TLR2 pathway in learning and memory. Analysis of the transcriptional effects of TLR2 activation reveals both common and unique transcriptional programs following heterodimer-specific TLR2 activation. These results imply that adult cognitive behavior could be influenced in part, by activation or alterations in the TLR2 pathway at birth.
Assuntos
Aprendizagem/fisiologia , Memória/fisiologia , Destreza Motora/fisiologia , Neurônios/metabolismo , Receptor 2 Toll-Like/metabolismo , Animais , Condicionamento Psicológico/fisiologia , Comportamento Exploratório/fisiologia , Medo/fisiologia , Camundongos , Camundongos Knockout , Teste de Desempenho do Rota-Rod , Aprendizagem Espacial/fisiologia , Receptor 2 Toll-Like/genéticaRESUMO
Recent findings suggest that Notch-1 signaling contributes to neuronal death in ischemic stroke, but the underlying mechanisms are unknown. Hypoxia inducible factor-1α (HIF-1α), a global regulator of cellular responses to hypoxia, can interact with Notch and modulate its signaling during hypoxic stress. Here we show that Notch signaling interacts with the HIF-1α pathway in the process of ischemic neuronal death. We found that a chemical inhibitor of the Notch-activating enzyme, γ-secretase, and a HIF-1α inhibitor, protect cultured cortical neurons against ischemic stress, and combined inhibition of Notch-1 and HIF-1α further decreased neuronal death. HIF-1α and Notch intracellular domain (NICD) are co-expressed in the neuronal nucleus, and co-immunoprecipitated in cultured neurons and in brain tissue from mice subjected to focal ischemic stroke. Overexpression of NICD and HIF-1α in cultured human neural cells enhanced cell death under ischemia-like conditions, and a HIF-1α inhibitor rescued the cells. RNA interference-mediated depletion of endogenous NICD and HIF-1α also decreased cell death under ischemia-like conditions. Finally, mice treated with inhibitors of γ-secretase and HIF-1α exhibited improved outcome after focal ischemic stroke, with combined treatment being superior to individual treatments. Additional findings suggest that the NICD and HIF-1α collaborate to engage pro-inflammatory and apoptotic signaling pathways in stroke.
Assuntos
Isquemia Encefálica/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neurônios/metabolismo , Receptor Notch1/metabolismo , Acidente Vascular Cerebral/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Morte Celular/fisiologia , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Infarto da Artéria Cerebral Anterior/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/metabolismoRESUMO
Toll-like receptors (TLR) are innate immune receptors typically activated by microbial-associated molecular patterns (MAMPs) during infection or damage-associated molecular patterns (DAMPs) as a result of tissue injury. Recent findings suggest that TLR2 and TLR4 signaling play important roles in developmental and adult neuroplasticity, and in learning and memory. In addition, activation of TLR2 and TLR4 worsens ischemic injury to the heart and brain in animal models of myocardial infarction and stroke. TLR activation is also implicated in thermoregulation and fever in response to infection. However, it is not known whether TLRs participate in the regulation of the sympathetic and/or parasympathetic components of the autonomic nervous system (ANS). Here we provide evidence that TLR2 and TLR4 influence autonomic regulation of heart rate (HR) body temperature and energy metabolism in mice. We show that mice lacking TLR2 or TLR4 exhibit reduced basal HR, which results from an increase of parasympathetic tone. In addition, thermoregulatory responses to stress are altered in TLR2-/- and TLR4-/- mice, and brown fat-dependent thermoregulation is altered in TLR4-/- mice. Moreover, TLR2-/- and TLR4-/- mice consume less food and exhibit a greater mass compared to wild type mice. Collectively, our findings suggest important roles for TLR2 and TLR4 in the ANS regulation of cardiovascular function, thermoregulation, and energy metabolism.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Animais , Temperatura Corporal , Regulação da Temperatura Corporal/fisiologia , Metabolismo Energético/fisiologia , Frequência Cardíaca/fisiologia , Masculino , Camundongos , Camundongos Knockout , Restrição Física , Estresse Psicológico/metabolismoRESUMO
Assessment of spatial learning abilities is central to behavioral neuroscience and a useful tool for animal model validation and drug development. However, biases introduced by the apparatus, environment, or experimentalist represent a critical challenge to the test validity. We have recently developed the Modified Barnes Maze (MBM) task, a spatial learning paradigm that overcomes inherent behavioral biases of animals in the classical Barnes maze. The specific combination of spatial strategies employed by mice is often considered representative of the level of cognitive resources used. Herein, we have developed a convolutional neural network-based classifier of exploration strategies in the MBM that can effectively provide researchers with enhanced insights into cognitive traits in mice. Following validation, we compared the learning performance of female and male C57BL/6J mice, as well as that of Ts65Dn mice, a model of Down syndrome, and 5xFAD mice, a model of Alzheimer's disease. Male mice exhibited more effective navigation abilities than female mice, reflected in higher utilization of effective spatial search strategies. Compared to wildtype controls, Ts65Dn mice exhibited delayed usage of spatial strategies despite similar success rates in completing this spatial task. 5xFAD mice showed increased usage of non-spatial strategies such as Circling that corresponded to higher latency to reach the target and lower success rate. These data exemplify the need for deeper strategy classification tools in dissecting complex cognitive traits. In sum, we provide a machine-learning-based strategy classifier that extends our understanding of mice's spatial learning capabilities while enabling a more accurate cognitive assessment.
Assuntos
Aprendizagem em Labirinto , Camundongos Endogâmicos C57BL , Redes Neurais de Computação , Aprendizagem Espacial , Animais , Masculino , Feminino , Camundongos , Aprendizagem Espacial/fisiologia , Modelos Animais de Doenças , Doença de Alzheimer , Comportamento AnimalRESUMO
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by expanded polyglutamine repeats in the huntingtin (Htt) protein. Mutant Htt may damage and kill striatal neurons by a mechanism involving reduced production of brain-derived neurotrophic factor (BDNF) and increased oxidative and metabolic stress. Because electroconvulsive shock (ECS) can stimulate the production of BDNF and protect neurons against stress, we determined whether ECS treatment would modify the disease process and provide a therapeutic benefit in a mouse model of HD. ECS (50 mA for 0.2 s) or sham treatment was administered once weekly to male N171-82Q Htt mutant mice beginning at 2 months of age. Endpoints measured included motor function, striatal and cortical pathology, and levels of protein chaperones and BDNF. ECS treatment delayed the onset of motor symptoms and body weight loss and extended the survival of HD mice. Striatal neurodegeneration was attenuated and levels of protein chaperones (Hsp70 and Hsp40) and BDNF were elevated in striatal neurons of ECS-treated compared with sham-treated HD mice. Our findings demonstrate that ECS can increase the resistance of neurons to mutant Htt resulting in improved functional outcome and extended survival. The potential of ECS as an intervention in subjects that inherit the mutant Htt gene merits further consideration.
Assuntos
Progressão da Doença , Eletrochoque , Doença de Huntington/patologia , Doença de Huntington/terapia , Mutação/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Doença de Huntington/genética , Masculino , Camundongos , Camundongos Transgênicos , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transdução de Sinais , Análise de SobrevidaRESUMO
Mice transgenic for antisense Notch and normal mice treated with inhibitors of the Notch-activating enzyme gamma-secretase showed reduced damage to brain cells and improved functional outcome in a model of focal ischemic stroke. Notch endangers neurons by modulating pathways that increase their vulnerability to apoptosis, and by activating microglial cells and stimulating the infiltration of proinflammatory leukocytes. These findings suggest that Notch signaling may be a therapeutic target for treatment of stroke and related neurodegenerative conditions.
Assuntos
Isquemia Encefálica/patologia , Encéfalo/patologia , Endopeptidases/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais/fisiologia , Acidente Vascular Cerebral/patologia , Secretases da Proteína Precursora do Amiloide , Animais , Apoptose , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Células Cultivadas , Endopeptidases/genética , Inibidores Enzimáticos/metabolismo , Humanos , Leucócitos/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microglia/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Ratos , Receptor Notch1/genética , Traumatismo por Reperfusão , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/terapia , Resultado do TratamentoRESUMO
Toll-like receptors (TLRs) are innate immune receptors that have recently emerged as regulators of neuronal survival and developmental neuroplasticity. Adult TLR3-deficient mice exhibited enhanced hippocampus-dependent working memory in the Morris water maze, novel object recognition, and contextual fear-conditioning tasks. In contrast, TLR3-deficient mice demonstrated impaired amygdala-related behavior and anxiety in the cued fear-conditioning, open field, and elevated plus maze tasks. Further, TLR3-deficient mice exhibited increased hippocampal CA1 and dentate gyrus volumes, increased hippocampal neurogenesis, and elevated levels of the AMPA receptor subunit GluR1 in the CA1 region of the hippocampus. In addition, levels of activated forms of the kinase ERK and the transcription factor CREB were elevated in the hippocampus of TLR3-deficient mice, suggesting that constitutive TLR3 signaling negatively regulates pathways known to play important roles in hippocampal plasticity. Direct activation of TLR3 by intracerebroventricular infusion of a TLR3 ligand impaired working memory, but not reference memory. Our findings reveal previously undescribed roles for TLR3 as a suppressor of hippocampal cellular plasticity and memory retention.
Assuntos
Hipocampo/fisiologia , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Receptor 3 Toll-Like/fisiologia , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Animais , Western Blotting , Proliferação de Células , Condicionamento Psicológico/fisiologia , Sinais (Psicologia) , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Giro Denteado/citologia , Giro Denteado/crescimento & desenvolvimento , Giro Denteado/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Medo/fisiologia , Feminino , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Camundongos , Camundongos Knockout , Atividade Motora/fisiologia , Neurogênese , Poli I-C/administração & dosagem , Poli I-C/farmacologia , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/metabolismoRESUMO
Introduction: Recently, interest has emerged in subjective cognitive decline (SCD) as a potential precursor to Alzheimer's disease (AD) dementia. Whether individuals with SCD harbor brain alterations in midlife, when AD-related pathology begins, is yet to be elucidated. Furthermore, the role of apolipoprotein ε4 (APOE ε4) allele, a robust AD risk factor, in the relationship between SCD and brain alterations is unknown. We examined whether APOE genotype modulates the association of SCD with brain measures in individuals at high AD risk. Methods: Middle-aged adults with parental history of AD dementia underwent magnetic resonance imaging (MRI) and the Memory Functioning Questionnaire. Regression analysis tested the extent to which SCD was associated with activation during an functional MRI (fMRI) working-memory task, and white-matter microstructure. APOE ε4 genotype was tested as a moderator. Results: Among APOE ε4 carriers, but not among non-carriers, SCD was associated with higher activation in the anterior cingulate (p = 0.003), inferior, middle, and superior frontal cortices (p = 0.041, p = 0.048, p = 0.037, respectively); and with lower fractional anisotropy in the uncinate fasciculus (p = 0.002), adjusting for age, sex, and education. Conclusion: In middle aged, cognitively normal individuals at high AD risk, higher SCD was associated with greater brain alterations possibly reflecting incipient AD pathology. When accompanied by a family history of AD and an APOE ε4 allele, SCD may have important clinical value, allowing a window for early intervention and for participants' stratification in AD prevention clinical trials.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Humanos , Mapas de Interação de Proteínas , Espécies Reativas de Oxigênio/metabolismo , Reprodutibilidade dos Testes , Transdução de SinaisRESUMO
Microglia, the primary brain-resident immune cells, protect the brain from various harmful pathogens, insulting and maintaining its homeostasis by phagocytosing extracellular particles. How microglia are metabolically regulated by their microenvironment remains largely elusive. Here, we investigated how extracellular lactate, which is abundant in the brain and dynamically changes in pathological states, affects microglial phagocytotic ability. We show that L-lactate reduces microglia phagocytic capacity in a Hydroxycarboxylic Acid Receptor 1 but not Monocarboxylate transporter 1-dependent manner. Our findings point to a potential role for extracellular lactate in suppressing the phagocytic activity of microglial cells in homeostasis and inflammatory conditions.