Browsing by Author "Matheu, Ander"
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Item Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimer’s mouse model by controlling β-amyloid production.(Scientific Reports, 2017-03-31) Colié, Sandra; Sarroca, Sara; Palenzuela Muñoz, Rocío; García, Idoia; Matheu, Ander; Corpas, Rubén; Dotti, Carlos G.; Esteban, José A.; Sanfeliu, Coral; Nebreda, Ángel R.Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a severe and progressive neuronal loss leading to cognitive dysfunctions. Previous reports, based on the use of chemical inhibitors, have connected the stress kinase p38α to neuroinflammation, neuronal death and synaptic dysfunction. To explore the specific role of neuronal p38α signalling in the appearance of pathological symptoms, we have generated mice that combine expression of the 5XFAD transgenes to induce AD symptoms with the downregulation of p38α only in neurons (5XFAD/p38α∆-N). We found that the neuronal-specific deletion of p38α improves the memory loss and long-term potentiation impairment induced by 5XFAD transgenes. Furthermore, 5XFAD/p38α∆-N mice display reduced amyloid-β accumulation, improved neurogenesis, and important changes in brain cytokine expression compared with 5XFAD mice. Our results implicate neuronal p38α signalling in the synaptic plasticity dysfunction and memory impairment observed in 5XFAD mice, by regulating both amyloid-β deposition in the brain and the relay of this accumulation to mount an inflammatory response, which leads to the cognitive deficits.Item Tumor-Derived Pericytes Driven by EGFR Mutations Govern the Vascular and Immune Microenvironment of Gliomas.(Cancer Research, 2021) Segura Collar, Berta; Garranzo Asensio, María; Herranz Sánchez, Beatriz; Hernández SanMiguel, Esther; Cejalvo, Teresa; S. Casas, Bárbara; Matheu, Ander; Pérez Núñez, Ángel; Sepúlveda Sánchez, Juan M.; Hernández Laín, Aurelio; Palma, Verónica; Gargini, Ricardo; Sánchez Gómez, PilarThe extraordinary plasticity of glioma cells allows them to contribute to different cellular compartments in tumor vessels, reinforcing the vascular architecture. It was recently revealed that targeting glioma-derived pericytes, which represent a big percentage of the mural cell population in aggressive tumors, increases the permeability of the vessels and improves the efficiency of chemotherapy. However, the molecular determinants of this transdifferentiation process have not been elucidated. Here we show that mutations in EGFR stimulate the capacity of glioma cells to function as pericytes in a BMX- (bone marrow and X-linked) and SOX9-dependent manner. Subsequent activation of platelet-derived growth factor receptor beta in the vessel walls of EGFR-mutant gliomas stabilized the vasculature and facilitated the recruitment of immune cells. These changes in the tumor microenvironment conferred a growth advantage to the tumors but also rendered them sensitive to pericyte-targeting molecules such as ibrutinib or sunitinib. In the absence of EGFR mutations, high-grade gliomas were enriched in blood vessels, but showed a highly disrupted blood–brain barrier due to the decreased BMX/SOX9 activation and pericyte coverage, which led to poor oxygenation, necrosis, and hypoxia. Overall, these findings identify EGFR mutations as key regulators of the glioma-to-pericyte transdifferentiation, highlighting the intricate relationship between the tumor cells and their vascular and immune milieu. Our results lay the foundations for a vascular-dependent stratification of gliomas and suggest different therapeutic vulnerabilities determined by the genetic status of EGFR.