Constitutive hippocampal cholesterol loss underlies poor cognition in old rodents

Cognitive decline is one of the many characteristics of aging. Reduced long-term potentiation (LTP) and long-term depression (LTD) are thought to be responsible for this decline, although the precise mechanisms underlying LTP and LTD dampening in the old remain unclear. We previously showed that aging is accompanied by the loss of cholesterol from the hippocampus, which leads to PI3K/Akt phosphorylation. Given that Akt de-phosphorylation is required for glutamate receptor internalization and LTD, we hypothesized that the decrease in cholesterol in neuronal membranes may contribute to the deficits in LTD typical of aging. Here, we show that cholesterol loss triggers p-Akt accumulation, which in turn perturbs the normal cellular and molecular responses induced by LTD, such as impaired AMPA receptor internalization and its reduced lateral diffusion. Electrophysiology recordings in brain slices of old mice and in anesthetized elderly rats demonstrate that the reduced hippocampal LTD associated with age can be rescued by cholesterol perfusion. Accordingly, cholesterol replenishment in aging animals improves hippocampal-dependent learning and memory in the water maze test.publishedVersionFil: Martín, Mauricio Gerardo. Consejo Superior de Investigaciones Científicas. Centro de Biología Molecular Severo Ochoa; España.Fil: Martín, Mauricio Gerardo. Universidad Autónoma de Madrid. Centro de Biología Molecular Severo Ochoa; España.Fil: Martín, Mauricio Gerardo. Katholieke Universiteit Leuven. Center for Human Genetics. VIB Center for the Biology of Disease; Bélgica.Fil: Ahmed, Tariq. Katholieke Universiteit Leuven. Faculty of Psychology and Educational Sciences. Laboratory of Biological Psychology; Bélgica.Fil: Korovaichuk, Alejandra. Consejo Superior de Investigaciones Científicas. Instituto Cajal. Departamento de Neurobiología Funcional y de Sistemas; España.Fil: Venero, César. Universidad Nacional de Educación a Distancia. Facultad de Psicología. Departamento de Psicobiología; España.Fil: Menchón, Silvia Adriana. Katholieke Universiteit Leuven. Center for Human Genetics. VIB Center for the Biology of Disease; Bélgica.Fil: Menchón, Silvia Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Física Enrique Gaviola; Argentina.Fil: Menchón, Silvia Adriana. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Salas, Isabel. Consejo Superior de Investigaciones Científicas. Centro de Biología Molecular Severo Ochoa; España.Fil: Salas, Isabel. Universidad Autónoma de Madrid. Centro de Biología Molecular Severo Ochoa; España.Fil: Salas, Isabel. Consejo Superior de Investigaciones Científicas. Centro de Biología Molecular Severo Ochoa; España.Fil: Munck, Sebastian. Katholieke Universiteit Leuven. Center for Human Genetics. VIB Center for the Biology of Disease; Bélgica.Fil: Herreras, Oscar. Consejo Superior de Investigaciones Científicas. Instituto Cajal. Departamento de Neurobiología Funcional y de Sistemas; España.Fil: Balschun, Detlef. Katholieke Universiteit Leuven. Faculty of Psychology and Educational Sciences. Laboratory of Biological Psychology; Bélgica.Fil: Dotti, Carlos Gerardo. Consejo Superior de Investigaciones Científicas. Centro de Biología Molecular Severo Ochoa; España.Fil: Dotti, Carlos Gerardo. Universidad Autónoma de Madrid. Centro de Biología Molecular Severo Ochoa; España.Fil: Dotti, Carlos Gerardo. Katholieke Universiteit Leuven. Center for Human Genetics. VIB Center for the Biology of Disease; Bélgica.Biofísic

Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup

As neurons age, they show a decrease in their ability to degrade proteins and membranes. Because undegraded material is a source of toxic products, defects in degradation are associated with reduced cell function and survival. However, there are very few dead neurons in the aging brain, suggesting the action of compensatory mechanisms. We show in this work that ageing neurons in culture show large multivesicular bodies (MVBs) filled with intralumenal vesicles (ILVs) and secrete more small extracellular vesicles than younger neurons. We also show that the high number of ILVs is the consequence of the accumulation of cholesterol in MVBs, which in turn is due to decreased levels of the cholesterol extruding protein NPC1. NPC1 down-regulation is the consequence of a combination of upregulation of the NPC1 repressor microRNA 33, and increased degradation, due to AktmTOR targeting of NPC1 to the phagosome. Although releasing more exosomes can be beneficial to old neurons, other cells, neighbouring and distant, can be negatively affected by the waste material they contain.Fil: Guix, Francesc X.. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Marrero Capitán, Ana. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; EspañaFil: Casadomé Perales, Álvaro. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; EspañaFil: Palomares Pérez, Irene. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; EspañaFil: Lopez del Castillo, Irene. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; EspañaFil: Miguel, Verónica. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; EspañaFil: Goedeke, Leigh. University of Yale; Estados UnidosFil: Martín, Mauricio Gerardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Lamas, Santiago. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; EspañaFil: Peinado, Héctor. Centro Nacional de Investigaciones Oncológicas; EspañaFil: Fernández Hernando, Carlos. University of Yale; Estados UnidosFil: Dotti, Carlos. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Científicas; Españ

A Roadmap for HEP Software and Computing R&D for the 2020s

Particle physics has an ambitious and broad experimental programme for the coming decades. This programme requires large investments in detector hardware, either to build new facilities and experiments, or to upgrade existing ones. Similarly, it requires commensurate investment in the R&D of software to acquire, manage, process, and analyse the shear amounts of data to be recorded. In planning for the HL-LHC in particular, it is critical that all of the collaborating stakeholders agree on the software goals and priorities, and that the efforts complement each other. In this spirit, this white paper describes the R&D activities required to prepare for this software upgrade.Peer reviewe

Neuronal activity controls Bdnf expression via Polycomb de-repression and CREB/CBP/JMJD3 activation in mature neurons

It has been recently described that in embryonic stem cells, the expression of some important developmentally regulated genes is repressed, but poised for fast activation under the appropriate stimuli. In this work we show that Bdnf promoters are repressed by Polycomb Complex 2 in mature hippocampal neurons, and basal expression is guaranteed by the coexistence with activating histone marks. Neuronal stimulation triggered by N-methyl-D-aspartate application induces the transcription of these promoters by H3K27Me3 demethylation and H3K27Me3 phosphorylation at Serine 28 leading to displacement of EZH2, the catalytic subunit of Polycomb Repressor Complex 2. Our data show that the fast transient expression of Bdnf promoters II and VI after neuronal stimulation is dependent on acetylation of histone H3K27 by CREB-p/CBP. Thus, regulatory mechanisms established during development seem to remain after differentiation controlling genes induced by different stimuli, as would be the case of early memory genes in mature neurons.Fil: Palomer, Ernest. Universidad Autonoma de Madrid. Centro de Biología Molecular; EspañaFil: Carretero, Javier. Universidad Autonoma de Madrid. Centro de Biología Molecular; EspañaFil: Benvegnù, Stefano. Universidad Autonoma de Madrid. Centro de Biología Molecular; EspañaFil: Dotti, Carlos G.. Universidad Autonoma de Madrid. Centro de Biología Molecular; EspañaFil: Martín, Mauricio Gerardo. Universidad Autonoma de Madrid. Centro de Biología Molecular; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentin

A Roadmap for HEP Software and Computing R&D for the 2020s

Particle physics has an ambitious and broad experimental programme for the coming decades. This programme requires large investments in detector hardware, either to build new facilities and experiments, or to upgrade existing ones. Similarly, it requires commensurate investment in the R&D of software to acquire, manage, process, and analyse the shear amounts of data to be recorded. In planning for the HL-LHC in particular, it is critical that all of the collaborating stakeholders agree on the software goals and priorities, and that the efforts complement each other. In this spirit, this white paper describes the R&D activities required to prepare for this software upgrade