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1.
Artigo em Inglês | MEDLINE | ID: mdl-38859788

RESUMO

BACKGROUND: Neurotrophins are essential factors for neural growth and function; they play a crucial role in neurodegenerative diseases where their expression levels are altered. Our previous research has demonstrated changes in synaptic plasticity and neurotrophin expression levels in a pharmacological model of Huntington's disease induced by 3-nitropropionic acid (3-NP). In the 3- NP-induced HD model, corticostriatal Long Term Depression (LTD) was impaired, but neurotrophin-3 (NT-3) restored striatal LTD. This study delves into the NT-3-induced signaling pathways involved in modulating and restoring striatal synaptic plasticity in cerebral slices from 3-NPinduced striatal degeneration in mice in vivo. METHODS: Phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways activated by NT-3 were analyzed by means of field electrophysiological recordings in brain slices from control and 3-NP treated in the presence of specific inhibitors of the signaling pathways. RESULTS: Using specific inhibitors, PLC, PI3K, and MEK/ERK signaling pathways contribute to NT3-mediated plasticity modulation in striatal tissue slices recorded from control animals. However, in the neurodegeneration model induced by 3-NP, the recovery of striatal LTD induced by NT-3 was prevented only by the PLC inhibitor. Moreover, the PLC signaling pathway appeared to trigger downstream activation of the endocannabinoid system, evidenced by AM 251, an inhibitor of the CB1 receptor, also hindered NT-3 plasticity recovery. CONCLUSION: Our finding highlights the specific involvement of the PLC pathway in the neuroprotective effects of NT-3 in mitigating synaptic dysfunction under neurodegenerative conditions.

2.
Neuroscience ; 518: 83-100, 2023 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35007692

RESUMO

In Alzheimer's disease (AD), two mutually exclusive amino-terminal-dependent conformations have been reported to occur during the aggregation of Tau protein into neurofibrillary tangles (NFTs). An early conformation of full-length Tau, involving the bending of the amino terminus over the third repeated domain, is recognized by the Alz-50 antibody, followed by a second conformation recognized by Tau-66 antibody that depends on the folding of the proline-rich region over the third repeated domain in a molecule partially truncated at the amino- and carboxyl-termini. α-1-antichymotrypsin (ACT) is an acute phase serum glycoprotein that accumulates abnormally in the brain of AD patients, and since it is considered to promote the in vitro and in vivo aggregation of amyloid-ß, we here seek further evidence that ACT may also contribute to the abnormal aggregation of Tau in AD. By analyzing brain samples from a population of AD cases under immunofluorescence and high-resolution confocal microscopy, we demonstrate here the abundant expression of ACT in hippocampal neurons, visualized as a granular diffuse accumulation, frequently reaching the nuclear compartment. In a significant number of these neurons, intracellular NFTs composed of abnormally phosphorylated and truncated Tau at Asp421 were also observed to coexist in separated regions of the cytoplasm. However, we found strong colocalization between ACT and diffuse aggregates of Tau-66-positive granules, which was not observed with Alz-50 antibody. These results suggest that ACT may play a role during the development of Tau conformational changes facilitating its aggregation during the formation of the neurofibrillary pathology in AD.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Proteínas tau/metabolismo , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Neurônios/metabolismo , Encéfalo/metabolismo , Anticorpos
3.
J Neurosci Res ; 97(12): 1665-1677, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31392756

RESUMO

Brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) are trophic factors belonging to the neurotrophin family; in addition to their trophic role, both neurotrophins play an important role in modulating corticostriatal synaptic transmission. Failures in BDNF supply and mitochondrial dysfunction are among the factors involved in the striatal degeneration that occurs in Huntington's disease (HD). While the effects of BDNF have been widely studied in striatal degeneration, the role of NT-4/5 has been less addressed. NT-4/5 does not appear to exert effects similar to those of BDNF in HD. The physiological roles of these molecules in corticostriatal transmission have been evaluated separately, and we have demonstrated that sequential exposure to both neurotrophins results in different modulatory effects on corticostriatal transmission depending on the exposure order. In the present study, we evaluated the effects of BDNF followed by NT-4/5 or NT-4/5 followed by BDNF on corticostriatal synaptic transmission with field recordings in a male mouse model of HD produced by in vivo treatment with the mitochondrial toxin 3-nitropropionic acid. Here, we show that these neurotrophins elicit an antagonistic or synergistic effect that depends on the activation of the truncated isoform or the stimulation of the full-length isoform of the tropomyosin receptor kinase B.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/fisiologia , Córtex Cerebral/fisiologia , Corpo Estriado/fisiologia , Doença de Huntington/fisiopatologia , Fatores de Crescimento Neural/fisiologia , Transmissão Sináptica , Animais , Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Doença de Huntington/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/administração & dosagem , Proteínas Tirosina Quinases/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo
4.
CNS Neurosci Ther ; 25(5): 621-631, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30666798

RESUMO

Neurotrophins are related to survival, growth, differentiation and neurotrophic maintenance as well as modulation of synaptic transmission in different regions of the nervous system. BDNF effects have been studied in the striatum due to the trophic role of BDNF in medium spiny neurons; however, less is known about the effects of NT-4/5, which is also present in the striatum and activates the TrkB receptor along with BDNF. If both neurotrophins are present in the striatum, the following question arises: What role do they play in striatal physiology? Thus, the aim of this study was to determine the physiological effect of the sequential application and coexistence of BDNF and NT-4/5 on the modulation of corticostriatal synapses. Our data demonstrated that neurotrophins exhibit differential effects depending on exposure order. BDNF did not modify NT-4/5 effect; however, NT-4/5 inhibited the effects of BDNF. Experiments carried out in COS-7 cells to understand the mechanisms of this antagonism, indicated that NT-4/5 exerts its inhibitory effect on BDNF by upregulating the TrkB.T1 and downregulating the TrkB-FL isoforms of the TrkB receptor.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Fatores de Crescimento Neural/metabolismo , Transmissão Sináptica/fisiologia , Animais , Células COS , Chlorocebus aethiops , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Fosfolipase C gama/metabolismo , Proteínas Tirosina Quinases/metabolismo , Sinapses/metabolismo , Técnicas de Cultura de Tecidos
5.
J Alzheimers Dis ; 65(4): 1185-1207, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30124450

RESUMO

Abnormal fibrillary aggregation of tau protein is a pathological condition observed in Alzheimer's disease and other tauopathies; however, the presence and pathological significance of early non-fibrillary aggregates of tau remain under investigation. In cell and animal models expressing normal or modified tau, toxic effects altering the structure and function of several membranous organelles have also been reported in the absence of fibrillary structures; however, how these abnormalities are produced is an issue yet to be addressed. In order to obtain more insights into the mechanisms by which tau may disturb intracellular membranous elements, we transiently overexpressed human full-length tau and several truncated tau variants in cultured neuroblastoma cells. After 48 h of transfection, either full-length or truncated tau forms produced significant fragmentation of the Golgi apparatus (GA) with no changes in cell viability. Noteworthy is that in the majority of cells exhibiting dispersion of the GA, a ring-shaped array of cortical or perinuclear microtubule (Mt) bundles was also generated under the expression of either variant of tau. In contrast, Taxol treatment of non-transfected cells increased the amount of Mt bundles but not sufficiently to produce fragmentation of the GA. Tau-induced ring-shaped Mt bundles appeared to be well-organized and stable structures because they were resistant to Nocodazole post-treatment and displayed a high level of tubulin acetylation. These results further indicate that a mechanical force generated by tau-induced Mt-bundling may be responsible for Golgi fragmentation and that the repeated domain region of tau may be the main promoter of this effect.


Assuntos
Citoesqueleto/metabolismo , Complexo de Golgi/metabolismo , Complexo de Golgi/ultraestrutura , Microtúbulos/metabolismo , Neuroblastoma/ultraestrutura , Proteínas tau/metabolismo , Brefeldina A/farmacologia , Metabolismo dos Carboidratos/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Glicoproteínas/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Mutação/genética , Neuroblastoma/patologia , Nocodazol/farmacologia , Compostos Orgânicos/metabolismo , Inibidores da Síntese de Proteínas/farmacologia , Transfecção , Proteínas tau/genética
6.
CNS Neurosci Ther ; 24(4): 353-363, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29453932

RESUMO

AIMS: Neurotrophin-3 (NT-3) is expressed in the mouse striatum; however, it is not clear the NT-3 role in striatal physiology. The expression levels of mRNAs and immune localization of the NT-3 protein and its receptor TrkC are altered in the striatum following damage induced by an in vivo treatment with 3-nitropropionic acid (3-NP), a mitochondrial toxin used to mimic the histopathological hallmarks of Huntington's disease (HD). The aim of this study was to evaluate the role of NT-3 on corticostriatal synaptic transmission and its plasticity in both the control and damaged striatum. METHODS: Corticostriatal population spikes were electrophysiologically recorded and striatal synaptic plasticity was induced by high-frequency stimulation. Further, the phosphorylation status of Trk receptors was tested under conditions that imitated electrophysiological experiments. RESULTS: NT-3 modulates both synaptic transmission and plasticity in the striatum; nonetheless, synaptic plasticity was modified by the 3-NP treatment, where instead of producing striatal long-term depression (LTD), long-term potentiation (LTP) was obtained. Moreover, the administration of NT-3 in the recording bath restored the plasticity observed under control conditions (LTD) in this model of striatal degeneration. CONCLUSION: NT-3 modulates corticostriatal transmission through TrkB stimulation and restores striatal LTD by signaling through its TrkC receptor.


Assuntos
Corpo Estriado/metabolismo , Doença de Huntington/metabolismo , Plasticidade Neuronal/fisiologia , Neurotrofina 3/metabolismo , Transmissão Sináptica/fisiologia , Animais , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Doença de Huntington/tratamento farmacológico , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Neurotrofina 3/administração & dosagem , Nitrocompostos , Propionatos , Proteínas Tirosina Quinases/metabolismo , RNA Mensageiro/metabolismo , Distribuição Aleatória , Receptor trkC/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Técnicas de Cultura de Tecidos
7.
Neural Plast ; 2016: 8782518, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27379187

RESUMO

In the last years it has been increasingly clear that KV-channel activity modulates neurotransmitter release. The subcellular localization and composition of potassium channels are crucial to understanding its influence on neurotransmitter release. To investigate the role of KV in corticostriatal synapses modulation, we combined extracellular recording of population-spike and pharmacological blockage with specific and nonspecific blockers to identify several families of KV channels. We induced paired-pulse facilitation (PPF) and studied the changes in paired-pulse ratio (PPR) before and after the addition of specific KV blockers to determine whether particular KV subtypes were located pre- or postsynaptically. Initially, the presence of KV channels was tested by exposing brain slices to tetraethylammonium or 4-aminopyridine; in both cases we observed a decrease in PPR that was dose dependent. Further experiments with tityustoxin, margatoxin, hongotoxin, agitoxin, dendrotoxin, and BDS-I toxins all rendered a reduction in PPR. In contrast heteropodatoxin and phrixotoxin had no effect. Our results reveal that corticostriatal presynaptic KV channels have a complex stoichiometry, including heterologous combinations KV1.1, KV1.2, KV1.3, and KV1.6 isoforms, as well as KV3.4, but not KV4 channels. The variety of KV channels offers a wide spectrum of possibilities to regulate neurotransmitter release, providing fine-tuning mechanisms to modulate synaptic strength.


Assuntos
Córtex Cerebral/fisiologia , Corpo Estriado/fisiologia , Terminações Pré-Sinápticas/fisiologia , Superfamília Shaker de Canais de Potássio/fisiologia , Canais de Potássio Shaw/fisiologia , Sinapses/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Masculino , Bloqueadores dos Canais de Potássio/farmacologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/fisiologia , Ratos , Ratos Wistar , Superfamília Shaker de Canais de Potássio/antagonistas & inibidores , Canais de Potássio Shaw/antagonistas & inibidores , Sinapses/efeitos dos fármacos
8.
J Alzheimers Dis ; 52(2): 463-82, 2016 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-27003208

RESUMO

Abnormal aggregation of Tau in glial cells has been reported in Alzheimer's disease (AD) and other tauopathies; however, the pathological significance of these aggregates remains unsolved to date. In this study, we evaluated whether full-length Tau (Tau441) and its aspartic acid421-truncated Tau variant (Tau421) produce alterations in the normal organization of the cytoskeleton and plasma membrane (PM) when transiently expressed in cultured C6-glial cells. Forty-eight hours post-transfection, abnormal microtubule bundling was observed in the majority of the cells, which expressed either Tau441 or Tau421. Moreover, both variants of Tau produced extensive PM blebbing associated with cortical redistribution of filamentous actin (F-Actin). These effects were reverted when Tau-expressing cells were incubated with drugs that depolymerize F-Actin. In addition, when glial cells showing Tau-induced PM blebbing were incubated with inhibitors of the Rho-associated protein kinase (ROCK) signaling pathway, both formation of abnormal PM blebs and F-Actin remodeling were avoided. All of these effects were initiated upstream by abnormal Tau-induced microtubule bundling, which may release the microtubule-bound guanine nucleotide exchange factor-H1 (GEF-H1) into the cytoplasm in order to activate its major effector RhoA-GTPase. These results may represent a new mechanism of Tau toxicity in which Tau-induced microtubule bundling produces activation of the Rho-GTPase-ROCK pathway that in turn mediates the remodeling of cortical Actin and PM blebbing. In AD and other tauopathies, these Tau-induced abnormalities may occur and contribute to the impairment of glial activity.


Assuntos
Actinas/metabolismo , Membrana Celular/metabolismo , Neuroglia/metabolismo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Proteínas tau/metabolismo , Actinas/efeitos dos fármacos , Animais , Western Blotting , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/patologia , Citoplasma/metabolismo , Eletroforese , Imunofluorescência , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Marcação In Situ das Extremidades Cortadas , Microscopia Confocal , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Transfecção , Tubulina (Proteína)/metabolismo , Proteínas tau/genética
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