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1.
ACS Chem Neurosci ; 12(22): 4249-4256, 2021 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-34738783

RESUMO

Alzheimer's disease (AD), the most common neurodegenerative disease, has limited treatment options. As such, extensive studies have been conducted to identify novel therapeutic approaches. We previously reported that rhynchophylline (Rhy), a small molecule EphA4 inhibitor, rescues impaired hippocampal synaptic plasticity and cognitive dysfunctions in APP/PS1 mice, an AD transgenic mouse model. To assess whether Rhy can be developed as an alternative treatment for AD, it is important to examine its pharmacokinetics and effects on other disease-associated pathologies. Here, we show that Rhy ameliorates amyloid plaque burden and reduces inflammation in APP/PS1 mice. Transcriptome analysis revealed that Rhy regulates various molecular pathways in APP/PS1 mouse brains associated with amyloid metabolism and inflammation, specifically the ubiquitin proteasome system, angiogenesis, and microglial functional states. These results show that Rhy, which is blood-brain barrier permeable, is beneficial to amyloid pathology and regulates multiple molecular pathways.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oxindóis , Placa Amiloide/tratamento farmacológico , Presenilina-1/genética
2.
Sci Rep ; 11(1): 4359, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33623128

RESUMO

Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no disease-modifying treatment. AD progression is characterized by cognitive decline, neuroinflammation, and accumulation of amyloid-beta (Aß) and neurofibrillary tangles in the brain, leading to neuronal and glial dysfunctions. Neuropeptides govern diverse pathophysiological processes and represent key players in AD pathogenesis, regulating synaptic plasticity, glial cell functions and amyloid pathology. Activation of the pro-opiomelanocortin (POMC)-derived neuropeptide and its receptor from the melanocortin receptor (MCR) family have previously been shown to rescue the impairment in hippocampus-dependent synaptic plasticity in the APP/PS1 mouse model of AD. However, the functional roles of MCR signaling in AD conditions, particularly in glial functions, are largely unknown. In this study, we investigated the potential benefits of MCR activation in AD. In APP/PS1 transgenic mice, we demonstrate that MCR activation mediated by the central administration of its agonist D-Tyr MTII substantially reduces Aß accumulation, while alleviating global inflammation and astrocytic activation, particularly in the hippocampus. MCR activation prominently reduces the A1 subtype of reactive astrocytes, which is considered a key source of astrocytic neurotoxicity in AD. Concordantly, MCR activation suppresses microglial activation, while enhancing their association with amyloid plaques. The blunted activation of microglia may contribute to the reduction in the neurotoxic phenotypes of astrocytes. Importantly, transcriptome analysis reveals that MCR activation restores the impaired homeostatic processes and microglial reactivity in the hippocampus in APP/PS1 mice. Collectively, our findings demonstrate the potential of MCR signaling as therapeutic target for AD.

3.
Proc Natl Acad Sci U S A ; 118(1)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33443211

RESUMO

Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.


Assuntos
Astrócitos/metabolismo , Região CA1 Hipocampal/metabolismo , Interleucina-33/metabolismo , Plasticidade Neuronal , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Proteína 4 Homóloga a Disks-Large/metabolismo , Técnicas de Inativação de Genes , Hipocampo/metabolismo , Homeostase , Interleucina-33/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Ratos , Sinapses/efeitos dos fármacos , Sinapses/genética , Sinapses/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Tetrodotoxina/farmacologia
4.
Sci Rep ; 10(1): 18746, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33127972

RESUMO

Dendrites, branched structures extending from neuronal cell soma, are specialized for processing information from other neurons. The morphogenesis of dendritic structures is spatiotemporally regulated by well-orchestrated signaling cascades. Dysregulation of these processes impacts the wiring of neuronal circuit and efficacy of neurotransmission, which contribute to the pathogeneses of neurological disorders. While Cdk5 (cyclin-dependent kinase 5) plays a critical role in neuronal dendritic development, its underlying molecular control is not fully understood. In this study, we show that p39, one of the two neuronal Cdk5 activators, is a key regulator of dendritic morphogenesis. Pyramidal neurons deficient in p39 exhibit aberrant dendritic morphology characterized by shorter length and reduced arborization, which is comparable to dendrites in Cdk5-deficient neurons. RNA sequencing analysis shows that the adaptor protein, WDFY1 (WD repeat and FYVE domain-containing 1), acts downstream of Cdk5/p39 to regulate dendritic morphogenesis. While WDFY1 is elevated in p39-deficient neurons, suppressing its expression rescues the impaired dendritic arborization. Further phosphoproteomic analysis suggests that Cdk5/p39 mediates dendritic morphogenesis by modulating various downstream signaling pathways, including PI3K/Akt-, cAMP-, or small GTPase-mediated signaling transduction pathways, thereby regulating cytoskeletal organization, protein synthesis, and protein trafficking.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Proteínas do Citoesqueleto/metabolismo , Dendritos/metabolismo , Proteínas Ligadas a Lipídeos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Western Blotting , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , AMP Cíclico/metabolismo , Quinase 5 Dependente de Ciclina/genética , Proteínas do Citoesqueleto/genética , Células HEK293 , Humanos , Proteínas Ligadas a Lipídeos/genética , Espectrometria de Massas , Camundongos , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Morfogênese/genética , Morfogênese/fisiologia , Sistema Nervoso/citologia , Sistema Nervoso/metabolismo , Neurônios/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia
5.
Cell Rep ; 31(3): 107530, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32320664

RESUMO

Impairment of microglial clearance activity contributes to beta-amyloid (Aß) pathology in Alzheimer's disease (AD). While the transcriptome profile of microglia directs microglial functions, how the microglial transcriptome can be regulated to alleviate AD pathology is largely unknown. Here, we show that injection of interleukin (IL)-33 in an AD transgenic mouse model ameliorates Aß pathology by reprogramming microglial epigenetic and transcriptomic profiles to induce a microglial subpopulation with enhanced phagocytic activity. These IL-33-responsive microglia (IL-33RMs) express a distinct transcriptome signature that is highlighted by increased major histocompatibility complex class II genes and restored homeostatic signature genes. IL-33-induced remodeling of chromatin accessibility and PU.1 transcription factor binding at the signature genes of IL-33RM control their transcriptome reprogramming. Specifically, disrupting PU.1-DNA interaction abolishes the microglial state transition and Aß clearance that is induced by IL-33. Thus, we define a PU.1-dependent transcriptional pathway that drives the IL-33-induced functional state transition of microglia, resulting in enhanced Aß clearance.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Interleucina-33/farmacologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Cromatina/genética , Cromatina/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-33/genética , Masculino , Camundongos , Camundongos Transgênicos , Microglia/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Recombinantes/farmacologia , Transativadores/metabolismo , Transcriptoma/efeitos dos fármacos
6.
Sci Rep ; 9(1): 1190, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718786

RESUMO

Major depressive disorders are emerging health problems that affect millions of people worldwide. However, treatment options and targets for drug development are limited. Impaired adult hippocampal neurogenesis is emerging as a key contributor to the pathology of major depressive disorders. We previously demonstrated that increasing the expression of the multifunctional scaffold protein Axis inhibition protein (Axin) by administration of the small molecule XAV939 enhances embryonic neurogenesis and affects social interaction behaviors. This prompted us to examine whether increasing Axin protein level can enhance adult hippocampal neurogenesis and thus contribute to mood regulation. Here, we report that stabilizing Axin increases adult hippocampal neurogenesis and exerts an antidepressant effect. Specifically, treating adult mice with XAV939 increased the amplification of adult neural progenitor cells and neuron production in the hippocampus under both normal and chronic stress conditions. Furthermore, XAV939 injection in mice ameliorated depression-like behaviors induced by chronic restraint stress. Thus, our study demonstrates that Axin/XAV939 plays an important role in adult hippocampal neurogenesis and provides a potential therapeutic approach for mood-related disorders.


Assuntos
Proteína Axina/metabolismo , Depressão/metabolismo , Neurogênese/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Proteína Axina/genética , Encéfalo/metabolismo , Diferenciação Celular/efeitos dos fármacos , Depressão/patologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/patologia , Modelos Animais de Doenças , Compostos Heterocíclicos com 3 Anéis/farmacologia , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Estresse Psicológico
7.
ACS Chem Neurosci ; 10(2): 872-879, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30221933

RESUMO

Alzheimer's disease is a progressive neurodegenerative disease, and its incidence is expected to increase owing to the aging population worldwide. Current therapies merely provide symptomatic relief. Therefore, interventions for AD that delay the disease onset or progression are urgently required. Recent genomics and functional studies suggest that immune/inflammatory pathways are involved in the pathogenesis of AD. Although many anti-inflammatory drug candidates have undergone clinical trials, most have failed. This might be because of our limited understanding of the pathological mechanisms of neuroinflammation in AD. However, recent advances in the understanding of immune/inflammatory pathways in AD and their regulatory mechanisms could open up new avenues for drug development targeting neuroinflammation. In this Review, we discuss the mechanisms and status of different anti-inflammatory drug candidates for AD that have undergone or are undergoing clinical trials and explore new opportunities for targeting neuroinflammation in AD drug development.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Anti-Inflamatórios/administração & dosagem , Sistemas de Liberação de Medicamentos/tendências , Descoberta de Drogas/tendências , Mediadores da Inflamação/metabolismo , Doença de Alzheimer/imunologia , Animais , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia
8.
Sci Rep ; 8(1): 7377, 2018 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-29743517

RESUMO

The receptor tyrosine kinase, erythropoietin-producing hepatocellular A4 (EphA4), was recently identified as a molecular target for Alzheimer's disease (AD). We found that blockade of the interaction of the receptor and its ligands, ephrins, alleviates the disease phenotype in an AD transgenic mouse model, suggesting that targeting EphA4 is a potential approach for developing AD interventions. In this study, we identified five FDA-approved drugs-ergoloid, cyproheptadine, nilotinib, abiraterone, and retapamulin-as potential inhibitors of EphA4 by using an integrated approach combining virtual screening with biochemical and cellular assays. We initially screened a database of FDA-approved drugs using molecular docking against the ligand-binding domain of EphA4. Then, we selected 22 candidate drugs and examined their inhibitory activity towards EphA4. Among them, five drugs inhibited EphA4 clustering induced by ephrin-A in cultured primary neurons. Specifically, nilotinib, a kinase inhibitor, inhibited the binding of EphA4 and ephrin-A at micromolar scale in a dosage-dependent manner. Furthermore, nilotinib inhibited the activation of EphA4 and EphA4-dependent growth cone collapse in cultured hippocampal neurons, demonstrating that the drug exhibits EphA4 inhibitory activity in cellular context. As demonstrated in our combined computational and experimental approaches, repurposing of FDA-approved drugs to inhibit EphA4 may provide an alternative fast-track approach for identifying and developing new treatments for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Simulação de Acoplamento Molecular , Pirimidinas/farmacologia , Receptor EphA4/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Androstenos/metabolismo , Androstenos/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Ciproeptadina/metabolismo , Ciproeptadina/farmacologia , Modelos Animais de Doenças , Diterpenos/metabolismo , Diterpenos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ligantes , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ligação Proteica , Domínios Proteicos , Pirimidinas/metabolismo , Receptor EphA4/metabolismo
9.
Proc Natl Acad Sci U S A ; 113(19): E2705-13, 2016 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-27091974

RESUMO

Alzheimer's disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of ß-amyloid (Aß) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aß levels and amyloid plaque deposition by promoting the recruitment and Aß phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1ß, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Encéfalo/fisiopatologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/fisiopatologia , Interleucina-33/administração & dosagem , Doença de Alzheimer/diagnóstico , Animais , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/diagnóstico , Citocinas/metabolismo , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/administração & dosagem , Resultado do Tratamento
10.
Nat Commun ; 6: 8665, 2015 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-26503494

RESUMO

Precise regulation of synaptic strength requires coordinated activity and functions of synaptic proteins, which is controlled by a variety of post-translational modification. Here we report that S-nitrosylation of p35, the activator of cyclin-dependent kinase 5 (Cdk5), by nitric oxide (NO) is important for the regulation of excitatory synaptic strength. While blockade of NO signalling results in structural and functional synaptic deficits as indicated by reduced mature dendritic spine density and surface expression of glutamate receptor subunits, phosphorylation of numerous synaptic substrates of Cdk5 and its activity are aberrantly upregulated following reduced NO production. The results show that the NO-induced reduction in Cdk5 activity is mediated by S-nitrosylation of p35, resulting in its ubiquitination and degradation by the E3 ligase PJA2. Silencing p35 protein in hippocampal neurons partially rescues the NO blockade-induced synaptic deficits. These findings collectively demonstrate that p35 S-nitrosylation by NO signalling is critical for regulating hippocampal synaptic strength.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Hipocampo/enzimologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Animais , Quinase 5 Dependente de Ciclina/genética , Hipocampo/metabolismo , Camundongos , Neurônios/enzimologia , Neurônios/metabolismo , Óxido Nítrico/metabolismo , Fosfotransferases/genética , Fosfotransferases/metabolismo , Processamento de Proteína Pós-Traducional , Proteólise , Ratos , Transmissão Sináptica
11.
PLoS One ; 10(7): e0133115, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26204446

RESUMO

During development, scaffold proteins serve as important platforms for orchestrating signaling complexes to transduce extracellular stimuli into intracellular responses that regulate dendritic spine morphology and function. Axin ("axis inhibitor") is a key scaffold protein in canonical Wnt signaling that interacts with specific synaptic proteins. However, the cellular functions of these protein-protein interactions in dendritic spine morphology and synaptic regulation are unclear. Here, we report that Axin protein is enriched in synaptic fractions, colocalizes with the postsynaptic marker PSD-95 in cultured hippocampal neurons, and interacts with a signaling protein Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in synaptosomal fractions. Axin depletion by shRNA in cultured neurons or intact hippocampal CA1 regions significantly reduced dendritic spine density. Intriguingly, the defective dendritic spine morphogenesis in Axin-knockdown neurons could be restored by overexpression of the small Rho-GTPase Cdc42, whose activity is regulated by CaMKII. Moreover, pharmacological stabilization of Axin resulted in increased dendritic spine number and spontaneous neurotransmission, while Axin stabilization in hippocampal neurons reduced the elimination of dendritic spines. Taken together, our findings suggest that Axin promotes dendritic spine stabilization through Cdc42-dependent cytoskeletal reorganization.


Assuntos
Proteína Axina/fisiologia , Espinhas Dendríticas/ultraestrutura , Transdução de Sinais/fisiologia , Proteína cdc42 de Ligação ao GTP/fisiologia , Animais , Proteína Axina/genética , Região CA1 Hipocampal/citologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Núcleo Celular/química , Células Cultivadas , Citosol/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Camundongos , Morfogênese , Neurogênese , Densidade Pós-Sináptica/química , Interferência de RNA , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Sinaptossomos/metabolismo
12.
Neuropsychopharmacology ; 40(8): 1877-87, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25649278

RESUMO

Compounds that have the ability to both strengthen synaptic function and facilitate neuroprotection are valuable cognitive enhancers that may improve health and quality of life, as well as retard age-related cognitive deterioration. Medicinal plants are an abundant source of potential cognitive enhancers. Here we report that anemoside A3 (AA3) isolated from Pulsatilla chinensis modulates synaptic connectivity in circuits central to memory enhancement. AA3 specifically modulates the function of AMPA-type glutamate receptors (AMPARs) by increasing serine phosphorylation within the GluA1 subunit, which is a modification required for the trafficking of GluA1-containing AMPARs to synapses. Furthermore, AA3 administration activates several synaptic signaling molecules and increases protein expressions of the neurotrophin brain-derived neurotrophic factor and monoamine neurotransmitters in the mouse hippocampus. In addition to acting through AMPARs, AA3 also acts as a non-competitive NMDA receptor (NMDAR) modulator with a neuroprotective capacity against ischemic brain injury and overexcitation in rats. These findings collectively suggest that AA3 possesses a unique ability to modulate the functions of both AMPARs and NMDARs. Concordantly, behavioral studies indicate that AA3 not only facilitates hippocampal long-term potentiation but also enhances spatial reference memory formation in mice. These multifaceted roles suggest that AA3 is an attractive candidate for further development as a cognitive enhancer capable of alleviating memory dysfunctions associated with aging and neurodegenerative diseases.


Assuntos
Cognição/efeitos dos fármacos , Hipocampo , Fármacos Neuroprotetores/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Saponinas/farmacologia , Sinapses/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Modelos Animais de Doenças , Reação de Fuga/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Técnicas In Vitro , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , N-Metilaspartato/farmacologia , Rede Nervosa/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Navegação Espacial/efeitos dos fármacos
13.
PLoS One ; 9(10): e110584, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25329792

RESUMO

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase, which plays critical roles in a wide spectrum of neuronal functions including neuronal survival, neurite outgrowth, and synapse development and plasticity. Cdk5 activity is controlled by its specific activators: p35 or p39. While knockout studies reveal that Cdk5/p35 is critical for neuronal migration during early brain development, functions of Cdk5/p35 have been unraveled through the identification of the interacting proteins of p35, most of which are Cdk5/p35 substrates. However, it remains unclear whether p35 can regulate neuronal functions independent of Cdk5 activity. Here, we report that a nuclear protein, nuclear hormone receptor coregulator (NRC)-interacting factor 1 (NIF-1), is a new interacting partner of p35. Interestingly, p35 regulates the functions of NIF-1 independent of Cdk5 activity. NIF-1 was initially discovered as a transcriptional regulator that enhances the transcriptional activity of nuclear hormone receptors. Our results show that p35 interacts with NIF-1 and regulates its nucleocytoplasmic trafficking via the nuclear export pathway. Furthermore, we identified a nuclear export signal on p35; mutation of this site or blockade of the CRM1/exportin-dependent nuclear export pathway resulted in the nuclear accumulation of p35. Intriguingly, blocking the nuclear export of p35 attenuated the nuclear accumulation of NIF-1. These findings reveal a new p35-dependent mechanism in transcriptional regulation that involves the nucleocytoplasmic shuttling of transcription regulators.


Assuntos
Transporte Ativo do Núcleo Celular/genética , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Neurônios/fisiologia , Proteínas Nucleares/biossíntese , Animais , Células COS , Chlorocebus aethiops , Citoplasma/genética , Citoplasma/metabolismo , Proteínas de Ligação a DNA , Regulação da Expressão Gênica no Desenvolvimento , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Carioferinas/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Fosforilação , Receptores Citoplasmáticos e Nucleares/genética , Fatores de Transcrição
14.
Proc Natl Acad Sci U S A ; 111(27): 9959-64, 2014 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-24958880

RESUMO

Alzheimer's disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-ß oligomers (Aß), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a small-molecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.


Assuntos
Doença de Alzheimer/fisiopatologia , Modelos Animais de Doenças , Hipocampo/fisiopatologia , Receptor EphA4/metabolismo , Sinapses/fisiologia , Doença de Alzheimer/metabolismo , Animais , Hipocampo/metabolismo , Camundongos , Camundongos Transgênicos , Receptor EphA4/genética , Sinapses/metabolismo
15.
J Neurosci ; 33(2): 464-72, 2013 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-23303927

RESUMO

Learning and memory require orchestrated regulation of both structural and functional synaptic plasticity in the hippocampus. While a neuropeptide alpha-melanocyte-stimulating hormone, α-MSH, has been implicated in memory acquisition and retention, the functional role of its cognate receptor, melanocortin-4 receptor (MC4R), in hippocampal-dependent synaptic plasticity has not been explored. In this study, we report that activation of MC4R enhances synaptic plasticity through the regulation of dendritic spine morphology and abundance of AMPA receptors. We show that activation of postsynaptic MC4R increases the number of mature dendritic spines and enhances surface expression of AMPA receptor subunit GluA1, resulting in synaptic accumulation of GluA1-containing AMPA receptors. Moreover, MC4R stimulates surface GluA1 trafficking through phosphorylation of GluA1 at Ser845 in a Gα(s)-cAMP/PKA-dependent manner. Blockade of protein kinase A (PKA) signaling abolishes the MC4R-mediated enhancement of neurotransmission and hippocampal long-term potentiation. Importantly, in vivo application of MC4R agonists increases LTP in the mouse hippocampal CA1 region. These findings reveal that MC4R in the hippocampus plays a critical role in the regulation of structural and functional plasticity.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Hipocampo/fisiologia , Plasticidade Neuronal/fisiologia , Receptor Tipo 4 de Melanocortina/fisiologia , Sinapses/fisiologia , Animais , Biotinilação , Western Blotting , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Primers do DNA , Fenômenos Eletrofisiológicos , Células HEK293 , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Aprendizagem/fisiologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Camundongos , Reação em Cadeia da Polimerase em Tempo Real , Receptores de AMPA/fisiologia , Técnicas Estereotáxicas , Transmissão Sináptica/fisiologia
16.
Neurosignals ; 21(1-2): 55-60, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22398430

RESUMO

Cyclin-dependent kinase 5 (Cdk5), a member of the cyclin-dependent kinase family, is critical for regulating neural development and neuronal survival. Dysregulation of Cdk5 is associated with abnormal expression of cell cycle-related proteins during neuronal apoptosis. We have previously found that p35, a Cdk5 activator, interacts with mSds3, an integral component of the histone deacetylase complex in vitro, suggesting a functional role of Cdk5 in gene regulation through modulation of chromatin integrity. In this study, we further demonstrate that Cdk5-dependent phosphorylation of mSds3 at Ser228 occurs in mouse brain nuclei. The expression of mSds3 protein and its interaction with Cdk5 activators is developmentally regulated in the mouse brain. Importantly, our findings suggest that the ability of Cdk5 to regulate activity deprivation-induced apoptosis of cerebellar granule neurons is likely mediated by the regulation of histone acetylation. Suppression of Cdk5 not only attenuates the induction of histone H3 acetylation and the aberrant upregulation of cyclin proteins in neurons after activity deprivation, but also results in protection of neurons against apoptotic cell death. Taken together, our findings suggest that Cdk5 regulates neuronal survival by precise epigenetic control through modulation of histone acetylation.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Neurônios/metabolismo , Acetilação , Animais , Morte Celular/fisiologia , Células Cultivadas , Cerebelo/metabolismo , Células HEK293 , Humanos , Camundongos , Fosforilação/fisiologia
17.
J Neurosci ; 32(24): 8263-9, 2012 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-22699907

RESUMO

Dendrites are the primary sites on neurons for receiving and integrating inputs from their presynaptic partners. Defects in dendrite development perturb the formation of neural circuitry and impair information processing in the brain. Extracellular cues are important for shaping the dendritic morphogenesis, but the underlying molecular mechanisms are not well understood. In this study, we examined the role of ARMS (ankyrin repeat-rich membrane spanning protein), also known as Kidins220 (kinase D-interacting substrate of 220 kDa), previously identified as a downstream target of neurotrophin and ephrin receptors, in dendrite development. We report here that knockdown of ARMS/Kidins220 by in utero electroporation impairs dendritic branching in mouse cerebral cortex, and silencing of ARMS/Kidins220 in primary rat hippocampal neurons results in a significant decrease in the length, number, and complexity of the dendritic arbors. Overexpression of cell surface receptor tyrosine kinases, including TrkB and EphB2, in ARMS/Kidins220-deficient neurons can partially rescue the defective dendritic phenotype. More importantly, we show that PI3K (phosphoinositide-3-kinase)- and Akt-mediated signaling pathway is crucial for ARMS/Kidins220-dependent dendrite development. Furthermore, loss of ARMS/Kidins220 significantly reduced the clustering of EphB2 receptor signaling complex in neurons. Our results collectively suggest that ARMS/Kidins220 is a key player in organizing the signaling complex to transduce the extracellular stimuli to cellular responses during dendrite development.


Assuntos
Proteínas de Membrana/fisiologia , Fosfoproteínas/fisiologia , Receptor trkB/fisiologia , Receptores da Família Eph/fisiologia , Animais , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/crescimento & desenvolvimento , Dendritos/metabolismo , Dendritos/fisiologia , Feminino , Técnicas de Silenciamento de Genes/métodos , Hipocampo/citologia , Hipocampo/fisiologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Neurogênese/fisiologia , Fosfoproteínas/genética , Cultura Primária de Células , Ratos , Receptores Proteína Tirosina Quinases/biossíntese , Transdução de Sinais/fisiologia
18.
Nat Neurosci ; 15(1): 39-47, 2011 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-22138645

RESUMO

Disrupted cortical neuronal migration is associated with epileptic seizures and developmental delay. However, the molecular mechanism by which disruptions of early cortical development result in neurological symptoms is poorly understood. Here we report α2-chimaerin as a key regulator of cortical neuronal migration and function. In utero suppression of α2-chimaerin arrested neuronal migration at the multipolar stage, leading to accumulation of ectopic neurons in the subcortical region. Mice with such migration defects showed an imbalance between excitation and inhibition in local cortical circuitry and greater susceptibility to convulsant-induced seizures. We further show that α2-chimaerin regulates bipolar transition and neuronal migration through modulating the activity of CRMP-2, a microtubule-associated protein. These findings establish a new α2-chimaerin-dependent mechanism underlying neuronal migration and proper functioning of the cerebral cortex and provide insights into the pathogenesis of seizure-related neurodevelopmental disorders.


Assuntos
Movimento Celular/fisiologia , Córtex Cerebral/metabolismo , Quimerina 1/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Animais , Córtex Cerebral/embriologia , Quimerina 1/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética
19.
Nat Neurosci ; 14(2): 181-9, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21186356

RESUMO

Homeostatic plasticity is crucial for maintaining neuronal output by counteracting unrestrained changes in synaptic strength. Chronic elevation of synaptic activity by bicuculline reduces the amplitude of miniature excitatory postsynaptic currents (mEPSCs), but the underlying mechanisms of this effect remain unclear. We found that activation of EphA4 resulted in a decrease in synaptic and surface GluR1 and attenuated mEPSC amplitude through a degradation pathway that requires the ubiquitin proteasome system (UPS). Elevated synaptic activity resulted in increased tyrosine phosphorylation of EphA4, which associated with the ubiquitin ligase anaphase-promoting complex (APC) and its activator Cdh1 in neurons in a ligand-dependent manner. APC(Cdh1) interacted with and targeted GluR1 for proteasomal degradation in vitro, whereas depletion of Cdh1 in neurons abolished the EphA4-dependent downregulation of GluR1. Knockdown of EphA4 or Cdh1 prevented the reduction in mEPSC amplitude in neurons that was a result of chronic elevated activity. Our results define a mechanism by which EphA4 regulates homeostatic plasticity through an APC(Cdh1)-dependent degradation pathway.


Assuntos
Regulação para Baixo/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Receptor EphA4/metabolismo , Receptores de AMPA/metabolismo , Complexos Ubiquitina-Proteína Ligase/metabolismo , Análise de Variância , Ciclossomo-Complexo Promotor de Anáfase , Animais , Bicuculina/farmacologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Eletrofisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Antagonistas de Receptores de GABA-A/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Potenciais Pós-Sinápticos em Miniatura/efeitos dos fármacos , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Interferente Pequeno , Receptores de AMPA/genética , Estatísticas não Paramétricas , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Complexos Ubiquitina-Proteína Ligase/genética , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/fisiologia
20.
J Neurosci ; 30(43): 14366-70, 2010 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-20980593

RESUMO

Precise regulation of cyclin-dependent kinase 5 (Cdk5), a member of the cyclin-dependent kinase family, is critical for proper neuronal development and functions. Cdk5 is activated through its association with the neuron-specific activator p35 or p39. Nonetheless, how its kinase activity is regulated in neurons is not well understood. In this study, we found that Cdk5 activity is regulated by S-nitrosylation, a post-translational modification of protein that affects a plethora of neuronal functions. S-nitrosylation of Cdk5 occurs at Cys83, which is one of the critical amino acids within the ATP-binding pocket of the kinase. Upon S-nitrosylation, Cdk5 exhibits reduced kinase activity, whereas mutation of Cys83 to Ala on Cdk5 renders the kinase refractory to such inhibition. Importantly, S-nitrosylated Cdk5 can be detected in the mouse brain, and blocking the S-nitrosylation of Cdk5 in cultured hippocampal neurons enhances dendritic growth and branching. Together, our findings reveal an important role of S-nitrosylation in regulating Cdk5 kinase activity and dendrite growth in neurons during development.


Assuntos
Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/fisiologia , Dendritos/fisiologia , Neurônios/fisiologia , Processamento de Proteína Pós-Traducional/genética , Processamento de Proteína Pós-Traducional/fisiologia , Animais , Biotina , Química Encefálica/fisiologia , Células Cultivadas , Cisteína/fisiologia , DNA Complementar/genética , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Humanos , Camundongos , Compostos Nitrosos/química , Proteínas Recombinantes de Fusão , Transfecção
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