1,721,007 research outputs found
CSIC Cicerón 15.4 Descifrando la ELA: Neuroinflamación y estrés oxidativo. Isabel Lastres Becker
No full textDatos técnicos: 2 minutos, color, español. Ficha técnica: Gabinete de Presidencia CSIC y Departamento de ComunicaciónPeer reviewe
New therapeutic strategies in Parkinson's disease: the transcription factor NRF2 as a target for dimethyl fumarate
No full textFractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis
No full textThe chemokine fractalkine modulates microglial responses in neurodegenerative diseases, including tauopathies, but the mechanistic processes and their relevance in human brain pathologies is not yet known. Here, we show that hippocampal HT22 cells expressing human TAU(P301L) mutant protein produce fractalkine, which in microglia activates AKT, inhibits glycogen synthase kinase-3 beta and upregulates the transcription factor NRF2/NFE2L2 and its target genes including heme oxygenase 1. In a mouse model of tauopathy based on stereotaxic delivery in hippocampus of an adeno-associated viral vector for expression of TAU(P301L), we confirmed that tau-injured neurons express fractalkine. NRF2- and fractalkine receptor-knockout mice did not express heme oxygenase 1 in microglia and exhibited increased microgliosis and astrogliosis in response to neuronal TAU(P301L) expression, demonstrating a crucial role of the fractalkine/NRF2/heme oxygenase 1 pathway in attenuation of the pro-inflammatory phenotype. The hippocampus of patients with Alzheimer's disease also exhibits increased expression of fractalkine in TAU-injured neurons that recruit microglia. These events correlated with increased levels of NRF2 and heme oxygenase 1 proteins, suggesting an attempt of the diseased brain to limit microgliosis. Our combined results indicate that fractalkine mobilizes NRF2 to limit over-activation of microglia and identify this new target to control unremitting neuroinflammation in tauopathies.Spanish MICINN [SAF2010-17822]; Ramon y Cajal contract (MICINN-RYC
Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy
No full textTauopathies are a group of neurodegenerative disorders where TAU protein is presented as aggregates or is abnormally phosphorylated, leading to alterations of axonal transport, neuronal death and neuroinflammation. Currently, there is no treatment to slow progression of these diseases. Here, we have investigated whether dimethyl fumarate (DMF), an inducer of the transcription factor NRF2, could mitigate tauopathy in a mouse model. The signaling pathways modulated by DMF were also studied in mouse embryonic fibroblast (MEFs) from wild type or KEAP1-deficient mice. The effect of DMF on neurodegeneration, astrocyte and microglial activation was examined in Nrf2+/+ and Nrf2â/â mice stereotaxically injected in the right hippocampus with an adeno-associated vector expressing human TAUP301L and treated daily with DMF (100 mg/kg, i.g) during three weeks. DMF induces the NRF2 transcriptional through a mechanism that involves KEAP1 but also PI3K/AKT/GSK-3-dependent pathways. DMF modulates GSK-3β activity in mouse hippocampi. Furthermore, DMF modulates TAU phosphorylation, neuronal impairment measured by calbindin-D28K and BDNF expression, and inflammatory processes involved in astrogliosis, microgliosis and pro-inflammatory cytokines production. This study reveals neuroprotective effects of DMF beyond disruption of the KEAP1/NRF2 axis by inhibiting GSK3 in a mouse model of tauopathy. Our results support repurposing of this drug for treatment of these diseases. Keywords: DMF, Inflammation, Neurodegeneration, NRF2, Oxidative stress, TAU/ GSK-
Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease
No full textAims: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, alpha-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation. Results: Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against alpha-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human alpha-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature. Innovation: These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy. Conclusion: DMF is ready for clinical validation in PD
Enfermedad de Alzheimer
No full textCharla divulgativa impartida en: Celebrate Brain Awareness Week: ¿Cómo estudian los científicos las enfermedades cerebrales?; sesión 1: "Herramientas científicas para el diagnóstico", celebrada en el Instituto de Investigaciones Biomédicas Alberto Sols (IIBM, CSIC-UAM) el 16 de marzo de 2017.Peer reviewe
Neuroinflamación y mitofagia en la enfermedad de Parkinson, y posibles estrategias terapéuticas para las tauopatías
Full text linkTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 19-04-2022Esta tesis tiene embargado el acceso al texto completo hasta el 19-10-2023La enfermedad de Parkinson (EP) es el segundo trastorno neurodegenerativo más común que se caracteriza por la degeneración de las neuronas dopaminérgicas de la Substantia Nigra pars compacta (SNpc) y la acumulación de agregados proteicos, llama-dos cuerpos de Lewy, siendo la proteína α-sinucleína (α-SYN) la más abundante. La neu-roinflamación y la disfunción mitocondrial también juegan un papel relevante en la EP. Además, determinados pacientes de la EP presentan agregados fosforilados de la proteí-na TAU, característica de las tauopatías. Así, este estudio se centra en investigar meca-nismos moleculares subyacentes a la EP, y en buscar un tratamiento para las tauopatías.
La neuroinflamación crónica de bajo grado es un evento clave en la EP donde la comu-nicación neurona-microglía es vital. Por ello, en este trabajo estudiamos por primera vez, el estado del sistema de la quimioquina fractalquina (CX3CL1) y su receptor CX3CR1 en la EP para, posteriormente, profundizar en la implicación del eje CX3CL1-CX3CR1 en la neurodegeneración y neuroinflamación asociada a la sobreexpresión de h-α-SYNWT o h-α-SYNA53T en ratones silvestre (Cx3cr1+/+) o deficientes (Cx3cr1-/-) para el receptor CX3CR1. La sobreexpresión de h-α-SYNWT o h-α-SYNA53T indujo neurodegeneración y neuroinflamación, exacerbadas en el caso de h-α-SYNA53T y potenciándose en los ratones Cx3cr1-/-; jugando CX3CR1 un papel en la neuroinflamación inducida por h-α-SYNA53T.
Otra característica subyacente a la EP es la disfunción mitocondrial, donde el proceso de la mitofagia—autofagia de mitocondrias dañadas—podría ser clave en el desarrollo de la enfermedad. Por ello, nos hemos planteado estudiar la mitofagia en nuestro modelo murino de la EP. Los resultados muestran que la sobreexpresión de h-α-SYNWT o h-α-SYNA53T conduce a una mitofagia disminuida en las neuronas dopaminérgicas de la SNpc, mientras que en los astrocitos reactivos se produce un aumento de la mitofagia.
Recientemente, se han descrito agregados fosforilados de TAU en pacientes de la EP con mutaciones en LRRK2; sugiriendo que la inhibición de la quinasa LRRK2 también podría ser una estrategia terapéutica para las tauopatías donde TAU se encuentra hiper-fosforilado. Por ello, analizamos los efectos del inhibidor de LRRK2, JZ1.40, en un modelo murino de tauopatía. JZ1.40 mejora el deterioro cognitivo inducido por la sobreexpre-sión de hTAUP301L, que se correlaciona con la prevención de la degeneración de las célu-las granulares del giro dentado; teniendo un efecto neuroprotector in vivo.
En conjunto, esta Tesis Doctoral ahonda en los mecanismos de neuroinflamación y mitofagia en la EP, y establece una posible estrategia terapéutica para las tauopatía
Editorial: Tau Protein: Mechanisms From Health to Degeneration
No full text© 2021 Lastres-Becker.In this Editorial, we are going to go through the essential points of the latest news published on the topic “TAU protein: mechanisms from health to degeneration.” In recent years, it has been shown that TAU protein is involved in multiple cellular mechanisms, which alterations are associated with neurodegenerative diseases called tauopathies. TAU is a neuronal microtubule-associated protein important for axonal transport which, under pathological conditions, forms aberrant assembly into insoluble aggregates. This led to synaptic dysfunction and neural cell death in a range of neurodegenerative disorders. Within this Editorial we will discover that the works presented are focus on three essential hallmarks of TAU: (1) TAU phosphorylation; (2) TAU oligomers and (3) TAU signaling (Figure 1). Altogether, finally, in this special issue, we will uncover several TAU-based therapies for these groups of diseases.This work was supported by a Spanish Ministry of Economy and Competitiveness Grants Refs. PID2019-105600RB-I00 to IL-B; General Council for Research and Innovation of the Community of Madrid and European Structural Funds Ref. S2017/BMD-3813-ELA_Madrid to IL-B. Fundación Tatiana Pérez de Guzmán el Bueno P-043-FTPGB 2020 to IL-B. Fundela (2019/00325/001) to IL-B
CX3CR1-deficient microglia shows impaired signalling of the transcription factor NRF2: Implications in tauopathies
Full text linkTAU protein aggregation is the main characteristic of neurodegenerative diseases known as tauopathies. Low-grade chronic inflammation is also another hallmark that indicates crosstalk between damaged neurons and glial cells. Previously, we have demonstrated that neurons overexpressing TAUP301L release CX3CL1, which activates the transcription factor NRF2 signalling to limit over-activation in microglial cells in vitro and in vivo. However, the connection between CX3CL1/CX3CR1 and NRF2 system and its functional implications in microglia are poorly described. We evaluated CX3CR1/NRF2 axis in the context of tauopathies and its implication in neuroinflammation. Regarding the molecular mechanisms that connect CX3CL1/CX3CR1 and NRF2 systems, we observed that in primary microglia from Cx3cr1-/- mice the mRNA levels of Nrf2 and its related genes were significantly decreased, establishing a direct linking between both systems. To determine functional relevance of CX3CR1, migration and phagocytosis assays were evaluated. CX3CR1-deficient microglia showed impaired cell migration and deficiency of phagocytosis, as previously described for NRF2-deficient microglia, reinforcing the idea of the relevance of the CX3CL1/CX3CR1 axis in these events. The importance of these findings was evident in a tauopathy mouse model where the effects of sulforaphane (SFN), an NRF2 inducer, were examined on neuroinflammation in Cx3cr1+/+ and Cx3cr1-/- mice. Interestingly, the treatment with SFN was able to modulate astrogliosis but failed to reduce microgliosis in Cx3cr1-/- mice. These findings suggest an essential role of the CX3CR1/NRF2 axis in microglial function and in tauopathies. Therefore, polymorphisms with loss of function in CX3CR1 or NRF2 have to be taken into account for the development of therapeutic strategies. Keywords: Inflammation, Neurodegeneration, TAU, Migration, TAM receptors, AXL, Microgliosis, Sulforaphan
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