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1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360966

RESUMO

Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Descoberta de Drogas/métodos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Medicina de Precisão/métodos
2.
Immunity ; 54(7): 1463-1477.e11, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34115964

RESUMO

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1ß production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.


Assuntos
Trifosfato de Adenosina/metabolismo , DNA Mitocondrial/biossíntese , Inflamassomos/efeitos dos fármacos , Metformina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia/prevenção & controle , Animais , COVID-19/metabolismo , COVID-19/prevenção & controle , Citocinas/genética , Citocinas/metabolismo , DNA Mitocondrial/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Metformina/uso terapêutico , Camundongos , Núcleosídeo-Fosfato Quinase/metabolismo , Pneumonia/metabolismo , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/prevenção & controle , SARS-CoV-2/patogenicidade
3.
Proc Natl Acad Sci U S A ; 118(15)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33833060

RESUMO

Parkinson's disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn-antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1ß (IL-1ß) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-ß peptide (Aß) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.

4.
J Neurosci ; 41(10): 2264-2273, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33483428

RESUMO

Synaptic and neuronal loss are major neuropathological characteristics of Parkinson's disease. Misfolded protein aggregates in the form of Lewy bodies, comprised mainly of α-synuclein (αSyn), are associated with disease progression, and have also been linked to other neurodegenerative diseases, including Lewy body dementia, Alzheimer's disease, and frontotemporal dementia. However, the effects of αSyn and its mechanism of synaptic damage remain incompletely understood. Here, we show that αSyn oligomers induce Ca2+-dependent release of glutamate from astrocytes obtained from male and female mice, and that mice overexpressing αSyn manifest increased tonic release of glutamate in vivo In turn, this extracellular glutamate activates glutamate receptors, including extrasynaptic NMDARs (eNMDARs), on neurons both in culture and in hippocampal slices of αSyn-overexpressing mice. Additionally, in patch-clamp recording from outside-out patches, we found that oligomerized αSyn can directly activate eNMDARs. In organotypic slices, oligomeric αSyn induces eNMDAR-mediated synaptic loss, which can be reversed by the drug NitroSynapsin. When we expose human induced pluripotent stem cell-derived cerebrocortical neurons to αSyn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from oligomeric αSyn-induced damage in our model systems, thus meriting further study for its therapeutic potential.SIGNIFICANCE STATEMENT Loss of synaptic function and ensuing neuronal loss are associated with disease progression in Parkinson's disease (PD), Lewy body dementia (LBD), and other neurodegenerative diseases. However, the mechanism of synaptic damage remains incompletely understood. α-Synuclein (αSyn) misfolds in PD/LBD, forming Lewy bodies and contributing to disease pathogenesis. Here, we found that misfolded/oligomeric αSyn releases excessive astrocytic glutamate, in turn activating neuronal extrasynaptic NMDA receptors (eNMDARs), thereby contributing to synaptic damage. Additionally, αSyn oligomers directly activate eNMDARs, further contributing to damage. While the FDA-approved drug memantine has been reported to offer some benefit in PD/LBD (Hershey and Coleman-Jackson, 2019), we find that the improved eNMDAR antagonist NitroSynapsin ameliorates αSyn-induced synaptic spine loss, providing potential disease-modifying intervention in PD/LBD.


Assuntos
Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , alfa-Sinucleína/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Células Cultivadas , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Sinapses/metabolismo , Sinapses/patologia , alfa-Sinucleína/farmacologia
5.
Mol Psychiatry ; 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32467645

RESUMO

Beginning at early stages, human Alzheimer's disease (AD) brains manifest hyperexcitability, contributing to subsequent extensive synapse loss, which has been linked to cognitive dysfunction. No current therapy for AD is disease-modifying. Part of the problem with AD drug discovery is that transgenic mouse models have been poor predictors of potential human treatment. While it is undoubtedly important to test drugs in these animal models, additional evidence for drug efficacy in a human context might improve our chances of success. Accordingly, in order to test drugs in a human context, we have developed a platform of physiological assays using patch-clamp electrophysiology, calcium imaging, and multielectrode array (MEA) experiments on human (h)iPSC-derived 2D cortical neuronal cultures and 3D cerebral organoids. We compare hiPSCs bearing familial AD mutations vs. their wild-type (WT) isogenic controls in order to characterize the aberrant electrical activity in such a human context. Here, we show that these AD neuronal cultures and organoids manifest increased spontaneous action potentials, slow oscillatory events (~1 Hz), and hypersynchronous network activity. Importantly, the dual-allosteric NMDAR antagonist NitroSynapsin, but not the FDA-approved drug memantine, abrogated this hyperactivity. We propose a novel model of synaptic plasticity in which aberrant neural networks are rebalanced by NitroSynapsin. We propose that hiPSC models may be useful for screening drugs to treat hyperexcitability and related synaptic damage in AD.

6.
J Neurochem ; 152(1): 61-71, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31520492

RESUMO

It has been suggested that extracellular alpha synuclein (αSyn) can mediate neuroinflammation in Parkinson's disease, and that αSyn affects B-cell maturation. However, the function of αSyn in T cells is poorly understood. We hypothesized that αSyn can affect CD4+ T-cell proliferation and activity. We found that αSyn deficiency exacerbates disease progression in 8 weeks old C57BL6/J EAE-induced mice, and that αSyn-deficient CD4+ T cells have increased pro-inflammatory response to myelin antigen relative to wild-type cells, as measured by cytokine secretion of interleukin IL-17 and interferon gamma. Furthermore, expression of αSyn on a background of αSyn knockout mitigates the inflammatory responses in CD4+ T cells. We discovered that elevated levels of Nurr1, a transcription factor belonging to the orphan nuclear receptor family, are associated with the pro-inflammatory profile of αSyn-deficient CD4+ T cells. In addition, we demonstrated that silencing of Nurr1 expression using an siRNA reduces IL-17 levels and increases the levels of IL-10, an anti-inflammatory cytokine. Study of αSyn-mediated cellular pathways in CD4+ T cells may provide useful insights into the development of pro-inflammatory responses in immunity, providing future avenues for therapeutic intervention.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Ativação Linfocitária/fisiologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/fisiologia , alfa-Sinucleína/deficiência , Animais , Proliferação de Células , Feminino , Regulação da Expressão Gênica , Inativação Gênica , Inflamação/imunologia , Inflamação/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Esclerose Múltipla/imunologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Células Th1/imunologia , alfa-Sinucleína/genética , alfa-Sinucleína/fisiologia
7.
Elife ; 82019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31782729

RESUMO

Human Alzheimer's disease (AD) brains and transgenic AD mouse models manifest hyperexcitability. This aberrant electrical activity is caused by synaptic dysfunction that represents the major pathophysiological correlate of cognitive decline. However, the underlying mechanism for this excessive excitability remains incompletely understood. To investigate the basis for the hyperactivity, we performed electrophysiological and immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures and cerebral organoids bearing AD-related mutations in presenilin-1 or amyloid precursor protein vs. isogenic gene corrected controls. In the AD hiPSC-derived neurons/organoids, we found increased excitatory bursting activity, which could be explained in part by a decrease in neurite length. AD hiPSC-derived neurons also displayed increased sodium current density and increased excitatory and decreased inhibitory synaptic activity. Our findings establish hiPSC-derived AD neuronal cultures and organoids as a relevant model of early AD pathophysiology and provide mechanistic insight into the observed hyperexcitability.


Assuntos
Potenciais de Ação , Doença de Alzheimer/fisiopatologia , Cérebro/citologia , Excitabilidade Cortical , Fenômenos Eletrofisiológicos , Células-Tronco Pluripotentes Induzidas/fisiologia , Neurônios/fisiologia , Precursor de Proteína beta-Amiloide/genética , Animais , Tamanho Celular , Células Cultivadas , Imunofluorescência , Humanos , Camundongos , Modelos Teóricos , Proteínas Mutantes/genética , Organoides , Presenilina-1/genética
8.
Trends Mol Med ; 25(2): 72-74, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30611669

RESUMO

Direct cell reprogramming, the process by which a somatic cell is converted to another cell type, can potentially circumvent epigenetic changes and proliferative stages resulting from de-differentiation. Recently, Matsuda et al. (Pioneer factor NeuroD1 rearranges transcriptional and epigenetic profiles to execute microglia-neuron conversion; Neuronin in press) demonstrated that expression of transcription factor NeuroD1 can convert mouse microglia to neurons, both in vitro and in vivo.


Assuntos
Microglia , Neurônios , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular , Reprogramação Celular , Epigênese Genética , Humanos , Camundongos
9.
J Genet ; 97(3): 729-751, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30027906

RESUMO

Parkinson's disease (PD) is a debilitating neurodegenerative disorder, for which people above the age of 60 show an increased risk. Although there has been great advancement in understanding the disease-related abnormalities in brain circuitry and development of symptomatic treatments, a cure for PD remains elusive. The discovery of PD associated gene mutations and environmental toxins have yielded animal models of the disease. These models could recapitulate several key aspects of PD, and provide more insights into the disease pathogenesis. They have also revealed novel aspects of the disease mechanism including noncell autonomous events and spreading of pathogenic protein species across the brain. Nevertheless, none of these models so far can comprehensively represent all aspects of the human disease. While the field is still searching for the perfect model system, recent developments in stem cell biology have provided a new dimension to modelling PD, especially doing it in a patient-specific manner. In the current review, we attempt to summarize the key findings in the areas discussed above, and highlight how the core PD pathology distinguishes itself from other neurodegenerative disorders while also resembling them in many aspects.


Assuntos
Modelos Animais de Doenças , Doença de Parkinson/patologia , Animais , Interação Gene-Ambiente , Humanos , Inflamação/patologia , Modelos Biológicos , Mutação/genética , Doença de Parkinson/genética
10.
J Neurochem ; 143(5): 584-594, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28921554

RESUMO

Parkinson's disease (PD) is a progressive neurodegenerative disorder, of which 1% of the hereditary cases are linked to mutations in DJ-1, an oxidative stress sensor. The pathological hallmark of PD is intercellular inclusions termed Lewy Bodies, composed mainly of α-Synuclein (α-Syn) protein. Recent findings have shown that α-Syn can be transmitted from cell to cell, suggesting an important role of microglia, as the main scavenger cells of the brain, in clearing α-Syn. We previously reported that the knock down (KD) of DJ-1 in microglia increased cells' neurotoxicity to dopaminergic neurons. Here, we discovered that α-Syn significantly induced elevated secretion of the proinflammatory cytokines IL-6 and IL-1ß and a significant dose-dependent elevation in the production of nitric oxide in DJ-1 KD microglia, compared to control microglia. We further investigated the ability of DJ-1 KD microglia to uptake and degrade soluble α-Syn, and discovered that DJ-1 KD reduces cell-surface lipid raft expression in microglia and impairs their ability to uptake soluble α-Syn. Autophagy is an important mechanism for degradation of intracellular proteins and organelles. We discovered that DJ-1 KD microglia exhibit an impaired autophagy-dependent degradation of p62 and LC3 proteins, and that manipulation of autophagy had less effect on α-Syn uptake and clearance in DJ-1 KD microglia, compared to control microglia. Further studies of the link between DJ-1, α-Syn uptake and autophagy may provide useful insights into the role of microglia in the etiology of the PD.


Assuntos
Autofagia/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Proteína Desglicase DJ-1/metabolismo , alfa-Sinucleína/farmacologia , Animais , Células Cultivadas , Citocinas/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Proteína Desglicase DJ-1/deficiência , alfa-Sinucleína/metabolismo
11.
Invest Ophthalmol Vis Sci ; 58(9): 3741-3749, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28738418

RESUMO

Purpose: Photoreceptor degeneration in the retina is a major cause of blindness in humans. Elucidating mechanisms of degenerative and neuroprotective pathways in photoreceptors should afford identification and development of therapeutic strategies. Methods: We used mouse genetic models and improved methods for retinal explant cultures. Retinas were enucleated from Mef2d+/+ and Mef2d-/- mice, stained for MEF2 proteins and outer nuclear layer thickness, and assayed for apoptotic cells. Chromatin immunoprecipitation (ChIP) assays revealed MEF2 binding, and RT-qPCR showed levels of transcription factors. We used AAV2 and electroporation to express genes in retinal explants and electroretinograms to assess photoreceptor functionality. Results: We identify a prosurvival MEF2D-PGC1α pathway that plays a neuroprotective role in photoreceptors. We demonstrate that Mef2d-/- mouse retinas manifest decreased expression of PGC1α and increased photoreceptor cell loss, resulting in the absence of light responses. Molecular repletion of PGC1α protects Mef2d-/- photoreceptors and preserves light responsivity. Conclusions: These results suggest that the MEF2-PGC1α cascade may represent a new therapeutic target for drugs designed to protect photoreceptors from developmental- and age-dependent loss.


Assuntos
Regulação da Expressão Gênica/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Células Fotorreceptoras de Vertebrados/fisiologia , Degeneração Retiniana/prevenção & controle , Envelhecimento , Animais , Apoptose , Sobrevivência Celular/fisiologia , Dependovirus/genética , Modelos Animais de Doenças , Eletroporação , Eletrorretinografia , Feminino , Terapia Genética , Marcação In Situ das Extremidades Cortadas , Fatores de Transcrição MEF2/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos , Reação em Cadeia da Polimerase em Tempo Real , Degeneração Retiniana/genética , Degeneração Retiniana/patologia
12.
Proc Natl Acad Sci U S A ; 114(20): E4048-E4056, 2017 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-28461502

RESUMO

Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d+/- retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of light-induced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Degeneração Retiniana/etiologia , Abietanos , Animais , Modelos Animais de Doenças , Haploinsuficiência , Luz/efeitos adversos , Fatores de Transcrição MEF2/genética , Camundongos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
13.
Neurobiol Dis ; 96: 84-94, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27544484

RESUMO

In Alzheimer's disease (AD), astrocytes undergo morphological changes ranging from atrophy to hypertrophy, but the effect of such changes at the functional level is still largely unknown. Here, we aimed to investigate whether alterations in astrocyte activity in AD are transient and depend on their microenvironment, or whether they are irreversible. We established and characterized a new protocol for the isolation of adult astrocytes and discovered that astrocytes isolated from old 5xFAD mice have higher GFAP expression than astrocytes derived from WT mice, as observed in vivo. We found high C1q levels in brain sections from old 5xFAD mice in close vicinity to amyloid plaques and astrocyte processes. Interestingly, while old 5xFAD astrocytes are impaired in uptake of soluble Aß42, this effect was reversed upon an addition of exogenous C1q, suggesting a potential role for C1q in astrocyte-mediated Aß clearance. Our results suggest that scavenger receptor B1 plays a role in C1q-facilitated Aß uptake by astrocytes and that expression of scavenger receptor B1 is reduced in adult old 5xFAD astrocytes. Furthermore, old 5xFAD astrocytes show impairment in support of neuronal growth in co-culture and neurotoxicity concomitant with an elevation in IL-6 expression. Further understanding of the impact of astrocyte impairment on AD pathology may provide insights into the etiology of AD.


Assuntos
Envelhecimento , Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Encéfalo/patologia , Regulação da Expressão Gênica/genética , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/metabolismo , Envelhecimento/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Antígeno CD11b/metabolismo , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Interleucina-6/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Mutação/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Receptores de Complemento/metabolismo
14.
J Neural Transm (Vienna) ; 122(10): 1409-19, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25894287

RESUMO

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor disturbances, appearance of Lewy bodies and dopaminergic neuronal death. The etiology of PD is unknown, although aging and neurotoxins are established risk factors. The activation of glial cells in the brain is the first defense mechanism against pathological events in neurodegenerative diseases, and neuroinflammation is suggested to play an important role in PD disease progression leading to dopaminergic neuronal degeneration. Gene mutations in several PD-related genes may affect up to 15% of the PD cases. These gene mutations can cause either loss or gain of function in their respective proteins leading to autosomal recessive and autosomal dominant PD, respectively. Most of the identified genes play a role in mitochondrial activity and integrity, and this was demonstrated mostly in neuronal cells. In this review, we aim to describe the link between PD-related genes, which are involved in mitochondrial function, and deleterious neuroinflammation.


Assuntos
Mitocôndrias/genética , Mitocôndrias/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/imunologia , Animais , Humanos , Neuroimunomodulação
15.
J Mol Neurosci ; 55(2): 430-6, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24994540

RESUMO

Low-level laser therapy (LLLT) has been used to treat inflammation, tissue healing, and repair processes. We recently reported that LLLT to the bone marrow (BM) led to proliferation of mesenchymal stem cells (MSCs) and their homing in the ischemic heart suggesting its role in regenerative medicine. The aim of the present study was to investigate the ability of LLLT to stimulate MSCs of autologous BM in order to affect neurological behavior and ß-amyloid burden in progressive stages of Alzheimer's disease (AD) mouse model. MSCs from wild-type mice stimulated with LLLT showed to increase their ability to maturate towards a monocyte lineage and to increase phagocytosis activity towards soluble amyloid beta (Aß). Furthermore, weekly LLLT to BM of AD mice for 2 months, starting at 4 months of age (progressive stage of AD), improved cognitive capacity and spatial learning, as compared to sham-treated AD mice. Histology revealed a significant reduction in Aß brain burden. Our results suggest the use of LLLT as a therapeutic application in progressive stages of AD and imply its role in mediating MSC therapy in brain amyloidogenic diseases.


Assuntos
Doença de Alzheimer/terapia , Terapia com Luz de Baixa Intensidade , Peptídeos beta-Amiloides/metabolismo , Animais , Cognição , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Monócitos/metabolismo , Fagocitose
16.
J Neurochem ; 129(3): 434-47, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24355073

RESUMO

DJ-1 is an oxidative stress sensor that localizes to the mitochondria when the cell is exposed to oxidative stress. DJ-1 mutations that result in gene deficiency are linked to increased risk of Parkinson's disease (PD). Activation of microglial stress conditions that are linked to PD may result in neuronal death. We postulated that DJ-1 deficiency may increase microglial neurotoxicity. We found that down-regulation of DJ-1 in microglia using an shRNA approach increased cell sensitivity to dopamine as measured by secreted pro-inflammatory cytokines such as IL-1ß and IL-6. Furthermore, we discovered that DJ-1-deficient microglia had increased monoamine oxidase activity that resulted in elevation of intracellular reactive oxygen species and nitric oxide leading to increased dopaminergic neurotoxicity. Rasagaline, a monoamine oxidase inhibitor approved for treatment of PD, reduced the microglial pro-inflammatory phenotype and significantly reduced neurotoxicity. Moreover, we discovered that DJ-1-deficient microglia have reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), previously suggested as a risk factor for pro-inflammation in neurodegenerative diseases. Further studies of DJ-1-mediated cellular pathways in microglia may contribute useful insights into the development of PD providing future avenues for therapeutic intervention


Assuntos
Indanos/farmacologia , Microglia/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Proteínas Oncogênicas/deficiência , Animais , Western Blotting , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Dopamina/toxicidade , Ensaio de Imunoadsorção Enzimática , Inflamação/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Neurotransmissores/toxicidade , Peroxirredoxinas , Fagocitose/efeitos dos fármacos , Fenótipo , Proteína Desglicase DJ-1 , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Brain Behav Immun ; 30: 176-85, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23313057

RESUMO

Oxidative stress plays an important role in the pathogenesis of various brain insults, including stroke. Astroglia are the main glial cells that play a fundamental role in maintaining the homeostasis of the CNS. They are important for protection from injury and aid the brain in functional recovery after injuries. It has been shown that the brain can be prepared to withstand an oxidative stress insult by a process known as preconditioning. We used primary astroglial cell culture to investigate whether preconditioning to mild oxidative stress and glucose deprivation (OSGD) can increase both astroglia survival and neuroprotective features. We found that preconditioning astroglia to mild OSGD increases astroglial survival of a second insult through activation of the NF-E2-related factor-2 (Nrf-2) pathway. Moreover, we found that Nrf-2 is highly expressed in adult brain astroglia and that preconditioning to OSGD in vivo, such as in a murine model of ischemic stroke, leads to a significant increase in astroglial Nrf-2 expression. Furthermore, we discovered an increase in neuroprotection, as measured by increased neuronal cell survival, following OSGD in the presence of medium from astroglia exposed to a mild OSGD condition. Interestingly, we discovered a significant increase in astroglial secretion of the anti-inflammatory cytokine IL-10 vs. the pro-inflammatory cytokine IL-1ß in mild vs. severe oxidative stress, respectively. We demonstrated that preconditioning astroglia to mild oxidative stress increases neuroprotection in an IL-10-dependent manner. By using tert-butylhydroquinone (tBHQ), a known specific activator of Nrf-2, we found that Nrf-2 can enhance IL-10 expression. Further studies of Nrf-2-mediated cellular pathways in astroglia through IL-10 may provide useful insights into the development of therapeutic interventions following oxidative stress insults such as ischemic stroke.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Sobrevivência Celular/fisiologia , Interleucina-10/metabolismo , Estresse Oxidativo/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular Tumoral , Células Cultivadas , Heme Oxigenase-1/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo
18.
Nat Chem Biol ; 8(8): 701-6, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22706200

RESUMO

Phenylketonuria (PKU) is characterized by phenylalanine accumulation and progressive mental retardation caused by an unknown mechanism. We demonstrate that at pathological concentrations, phenylalanine self-assembles into fibrils with amyloid-like morphology and well-ordered electron diffraction. These assemblies are specifically recognized by antibodies, show cytotoxicity that can be neutralized by the antibodies and are present in the hippocampus of model mice and in parietal cortex brain tissue from individuals with PKU. This is, to our knowledge, the first demonstration that a single amino acid can form amyloid-like deposits, suggesting a new amyloidosis-like etiology for PKU.


Assuntos
Amiloide/química , Amiloide/metabolismo , Fenilalanina/química , Fenilalanina/metabolismo , Fenilcetonúrias/metabolismo , Animais , Anticorpos , Biofísica , Células CHO , Cricetinae , Hipocampo , Humanos , Imunoprecipitação , Camundongos , Modelos Moleculares , Lobo Parietal , Conformação Proteica , Coelhos
19.
Ann Neurol ; 69(1): 170-80, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21280087

RESUMO

OBJECTIVE: The cleavage of amyloid precursor protein by γ-secretase is an important aspect of the pathogenesis of Alzheimer's disease. γ-Secretase also cleaves other membrane proteins (eg, Notch), which control cell development and homeostasis. Presenilin 1 and 2 are considered important determinants of the γ-secretase catalytic site. Our aim was to investigate whether γ-secretase can be important for microglial phagocytosis of Alzheimer's disease ß-amyloid. METHODS: We investigated the role of γ-secretase in microglia activity toward ß-amyloid phagocytosis in cell culture using γ-secretase inhibitors and small hairpin RNA and presenilin-deficient mice. RESULTS: We found that γ-secretase inhibitors impair microglial activity as measured in gene expression, protein levels, and migration ability, which resulted in a reduction of soluble ß-amyloid phagocytosis. Moreover, microglia deficient in presenilin 1 and 2 showed impairment in phagocytosis of soluble ß-amyloid. Dysfunction in the γ-secretase catalytic site led to an impairment in clearing insoluble ß-amyloid from brain sections taken from an Alzheimer's disease mouse model when compared to microglia from wild-type mice. INTERPRETATION: We suggest for the first time, a dual role for γ-secretase in Alzheimer's disease. One role is the cleavage of the amyloid precursor protein for pathologic ß-amyloid production and the other is to regulate microglia activity that is important for clearing neurotoxic ß-amyloid deposits. Further studies of γ-secretase-mediated cellular pathways in microglia may provide useful insights into the development of Alzheimer's disease and other neurodegenerative diseases, providing future avenues for therapeutic intervention.


Assuntos
Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/fisiologia , Peptídeos beta-Amiloides/biossíntese , Placa Amiloide/patologia , Presenilinas/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Células Cultivadas , Macrófagos Peritoneais/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/fisiologia , Fagocitose/fisiologia , Placa Amiloide/metabolismo , Presenilinas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Transfecção/métodos
20.
Artigo em Inglês | MEDLINE | ID: mdl-20706642

RESUMO

Toll-like receptors (TLRs) are known to be expressed by innate immune response cells and to play a critical role in their activation against foreign pathogens. It was recently suggested that TLRs have an important role in the crosstalk between neurons and glial cells in the central nervous system (CNS). TLR signaling was reported to be associated with a yin-yang effect in the CNS. While TLR signaling was linked to neurogenesis, it was also found to be involved in the pathogenesis of neurodegenerative diseases. This paper will focus on TLR signaling in glial cells in neurodegenerative diseases such as Alzheimer's disease, prion diseases, amyotrophic lateral sclerosis, and Parkinson's disease. Understanding the pattern of TLR signaling in the glial cells may lead to the identification of new targets for therapeutic application.


Assuntos
Amiloidose , Doenças Neurodegenerativas , Neuroglia/metabolismo , Transdução de Sinais/fisiologia , Receptores Toll-Like/metabolismo , Amiloidose/metabolismo , Amiloidose/patologia , Amiloidose/terapia , Animais , Humanos , Imunidade Inata/imunologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/terapia , Neurogênese/fisiologia , Neurônios/metabolismo
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