Abellanas-Sánchez, M.A. (Miguel Ángel)
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- Dopamine receptor D3 expression is altered in CD4(+) T-cells from parkinson's disease patients and its pharmacologic inhibition attenuates the motor impairment in a mouse model(2019) Montoya, A. (Andro); Pacheco, R. (Rodrigo); Abellanas-Sánchez, M.A. (Miguel Ángel); Aymerich-Soler, M.S. (María Soledad); Contreras, F. (Francisco); Franco, R. (Rafael); Choval, O. (Ornella); Villagra, R. (Roque); Henriquez, C. (Claudio); Ugalde, V. (Valentina); Elgueta, D. (Daniela); Prado, C. (Carolina)Neuroinflammation constitutes a fundamental process involved in Parkinson's disease (PD). Microglial cells play a central role in the outcome of neuroinflammation and consequent neurodegeneration of dopaminergic neurons in the substantia nigra. Current evidence indicates that CD4(+) T-cells infiltrate the brain in PD, where they play a critical role determining the functional phenotype of microglia, thus regulating the progression of the disease. We previously demonstrated that mice bearing dopamine receptor D3 (DRD3)-deficient CD4(+) T-cells are completely refractory to neuroinflammation and consequent neurodegeneration induced by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study we aimed to determine whether DRD3-signalling is altered in peripheral blood CD4(+) T-cells obtained from PD patients in comparison to healthy controls (HC). Furthermore, we evaluated the therapeutic potential of targeting DRD3 confined to CD4(+) T-cells by inducing the pharmacologic antagonism or the transcriptional inhibition of DRD3-signalling in a mouse model of PD induced by the chronic administration of MPTP and probenecid (MPTPp). In vitro analyses performed in human cells showed that the frequency of peripheral blood Th1 and Th17 cells, two phenotypes favoured by DRD3-signalling, were significantly increased in PD patients. Moreover, native CD4(+) T-cells obtained from PD patients displayed a significant higher Th1 -biased differentiation in comparison with those naive CD4(+) T-cells obtained from HC. Nevertheless, DRD3 expression was selectively reduced in CD4(+) T-cells obtained from PD patients. The results obtained from in vivo experiments performed in mice show that the transference of CD4(+) T-cells treated ex vivo with the DRD3-selective antagonist PG01037 into MPTPp-mice resulted in a significant reduction of motor impairment, although without significant effect in neurodegeneration. Conversely, the transference CD4(+) T-cells transduced ex vivo with retroviral pArtículos codifying for an shRNA for DRD3 into MPTPp-mice had no effects neither in motor impairment nor in neurodegeneration. Notably, the systemic antagonism of DRD3 significantly reduced both motor impairment and neurodegeneration in MPTPp mice. Our findings show a selective alteration of DRD3-signalling in CD4(+) T-cells from PD patients and indicate that the selective DRD3-antagonism in this subset of lymphocytes exerts a therapeutic effect in parkinsonian animals dampening motor impairment.
- Midbrain microglia mediate a specific immunosuppressive response under inflammatory conditions(Springer Science and Business Media LLC, 2019) Vilas, A. (Amaia); Abellanas-Sánchez, M.A. (Miguel Ángel); San-Martín-Uriz, P. (Patxi); Zamarbide-González, M. (Marta); Aymerich-Soler, M.S. (María Soledad); Basurco, L. (Leyre); Hervas-Stubbs, S. (Sandra); Garcia-Granero, M. (Marta); Mengual, E. (Elisa); Clavero, P. (P.); Luquin, E. (Esther)Background: Inflammation is a critical process for the progression of neuronal death in neurodegenerative disorders. Microglia play a central role in neuroinflammation and may affect neuron vulnerability. Next generation sequencing has shown the molecular heterogeneity of microglial cells; however, the variability in their response to pathological inputs remains unknown. Methods: To determine the effect of an inflammatory stimulus on microglial cells, lipopolysaccharide (LPS) was administered peripherally to mice and the inflammatory status of the cortex, hippocampus, midbrain, and striatum was assessed. Microglial activation and interaction with the immune system were analyzed in single cell suspensions obtained from the different brain regions by fluorescence-activated cell sorting, next generation RNA sequencing, real-time PCR, and immunohistochemical techniques. Antigen-presenting properties of microglia were evaluated by the ability of isolated cells to induce a clonal expansion of CD4+ T cells purified from OT-II transgenic mice. Results: Under steady-state conditions, the midbrain presented a high immune-alert state characterized by the presence of two unique microglial subpopulations, one expressing the major histocompatibility complex class II (MHC-II) and acting as antigen-presenting cells and another expressing the toll-like receptor 4 (TLR4), and by the presence of a higher proportion of infiltrating CD4+ T cells. This state was not detected in the cortex, hippocampus, or striatum. Systemic LPS administration induced a general increase in classic pro-inflammatory cytokines, in coinhibitory programmed death ligand 1 (PD-L1), and in cytotoxic T lymphocyte antigen 4 (CTLA-4) receptors, as well as a decrease in infiltrating effector T cells in all brain regions. Interestingly, a specific immune-suppressive response was observed in the midbrain which was characterized by the downregulation of MHC-II microglial expression, the upregulation of the anti-inflammatory cytokines IL10 and TGFβ, and the increase in infiltrating regulatory T cells. Conclusions: These data show that the midbrain presents a high immune-alert state under steady-state conditions that elicits a specific immune-suppressive response when exposed to an inflammatory stimulus. This specific inflammatory tone and response may have an impact in neuronal viability
- CB2 Receptors and Neuron–Glia Interactions Modulate Neurotoxicity Generated by MAGL Inhibition(2020) Abellanas-Sánchez, M.A. (Miguel Ángel); Aymerich-Soler, M.S. (María Soledad); Baltanas, A. (Ana); Íñigo-Marco, I. (Ignacio); Arrasate, M. (Montserrat); Rojo-Bustamante, E. (Estefania); Luquin, E. (Esther); Vinueza-Gavilanes, R. (Rodrigo)Monoacylglycerol lipase inhibition (MAGL) has emerged as an interesting therapeutic target for neurodegenerative disease treatment due to its ability to modulate the endocannabinoid system and to prevent the production of proinflammatory mediators. To obtain a beneficial response, it is necessary to understand how this inhibition affects the neuron–glia crosstalk and neuron viability. In this study, the effect of MAGL inhibition by KML29 was evaluated in two types of rat cortical primary cultures; mixed cultures, including neuron and glial cells, and neuron-enriched cultures. The risk of neuronal death was estimated by longitudinal survival analysis. The spontaneous neuronal risk of death in culture was higher in the absence of glial cells, a process that was enhanced by KML29 addition. In contrast, neuronal survival was not compromised by MAGL inhibition in the presence of glial cells. Blockade of cannabinoid type 2 (CB2) receptors expressed mainly by microglial cells did not affect the spontaneous neuronal death risk but decreased neuronal survival when KML29 was added. Modulation of cannabinoid type 1 (CB1) receptors did not affect neuronal survival. Our results show that neuron–glia interactions are essential for neuronal survival. CB2 receptors play a key role in these protective interactions when neurons are exposed to toxic conditions.
- Expression of endothelial NOX5 alters the integrity of the blood-brain barrier and causes loss of memory in aging mice(2021) Abellanas-Sánchez, M.A. (Miguel Ángel); Ramirez, M.J. (María Javier); Aymerich-Soler, M.S. (María Soledad); Solas, M. (Maite); Pejenaute-Martínez-de-Lizarrondo, Á. (Álvaro); García-Lacarte, M. (Marcos); Marqués-Cantero, J. (Javier); Cortés-Jiménez, A. (Adriana); Zalba, G. (Guillermo)Blood-Brain barrier (BBB) disruption is a hallmark of central nervous system (CNS) dysfunction, and oxidative stress is one of the molecular mechanisms that may underlie this process. NADPH oxidases (NOX) are involved in oxidative stress-mediated vascular dysfunction and participate in the pathophysiology of its target organs. The NADPH oxidase 5 (NOX5) isoform is absent in rodents, and although little is known about the role it may play in disrupting the BBB, it has recently been implicated in experimental stroke. Our aim was to investigate the role of NADPH oxidase 5 (NOX5) in promoting vascular alterations and to identify its impact on the cognitive status of aged mice. No differences were detected in the arterial blood pressure or body weight between knock-in mice expressing endothelial NOX5 and the control mice. The Morris water maze test showed memory impairments in the aged knock-in mice expressing NOX5 compared with their control littermates. For assessing the BBB integrity, we studied the protein expression of two tight junction (TJ) proteins: Zonula occludens-1 (ZO-1) and occludin. Compared to the control animals, Aged NOX5 mice exhibited reduced levels of both proteins, demonstrating an alteration of the BBB integrity. Our data indicate that vascular NOX5 may favor behavioral changes with aging through oxidative stress-mediated BBB breakdown.
- Microglia and astrocyte activation is region-dependent in the alfa-synuclein mouse model of Parkinson's disease(Wiley, 2023) Vilas, A. (Amaia); González-Aseguinolaza, G. (Gloria); Alonso-Roldán, M.M. (Marta María); Vales, A. (África); Abellanas-Sánchez, M.A. (Miguel Ángel); San-Martín-Uriz, P. (Patxi); Aymerich-Soler, M.S. (María Soledad); Ayerra, L. (Leyre); Basurco, L. (Leyre); Hervas-Stubbs, S. (Sandra); Hernaez, M. (Mikel); Mengual, E. (Elisa); Clavero, P. (P.); Arrasate, M. (Montserrat); Tamayo, I. (Ibon); Conde, E. (Enrique); Luquin, E. (Esther); Vinueza-Gavilanes, R. (Rodrigo)Inflammation is a common feature in neurodegenerative diseases that contributes to neuronal loss. Previously, we demonstrated that the basal inflammatory tone differed between brain regions and, consequently, the reaction generated to a pro-inflammatory stimulus was different. In this study, we assessed the innate immune reaction in the midbrain and in the striatum using an experimental model of Parkinson's disease. An adeno-associated virus serotype 9 expressing the α-synuclein and mCherry genes or the mCherry gene was administered into the substantia nigra. Myeloid cells (CD11b+ ) and astrocytes (ACSA2+ ) were purified from the midbrain and striatum for bulk RNA sequencing. In the parkinsonian midbrain, CD11b+ cells presented a unique anti-inflammatory transcriptomic profile that differed from degenerative microglia signatures described in experimental models for other neurodegenerative conditions. By contrast, striatal CD11b+ cells showed a pro-inflammatory state and were similar to disease-associated microglia. In the midbrain, a prominent increase of infiltrated monocytes/macrophages was observed and, together with microglia, participated actively in the phagocytosis of dopaminergic neuronal bodies. Although striatal microglia presented a phagocytic transcriptomic profile, morphology and cell density was preserved and no active phagocytosis was detected. Interestingly, astrocytes presented a pro-inflammatory fingerprint in the midbrain and a low number of differentially displayed transcripts in the striatum. During α-synuclein-dependent degeneration, microglia and astrocytes experience context-dependent activation states with a different contribution to the inflammatory reaction. Our results point towards the relevance of selecting appropriate cell targets to design neuroprotective strategies aimed to modulate the innate immune system during the active phase of dopaminergic degeneration.