Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1

Genetic Alzheimer’s disease (AD) risk factors associate with reduced defensive amyloid β plaque-associated microglia (AβAM), but the contribution of modifiable AD risk factors to microglial dysfunction is unknown. In AD mouse models, we observe concomitant activation of the hypoxia-inducible factor 1 (HIF1) pathway and transcription of mitochondrial-related genes in AβAM, and elongation of mitochondria, a cellular response to maintain aerobic respiration under low nutrient and oxygen conditions. Overactivation of HIF1 induces microglial quiescence in cellulo, with lower mitochondrial respiration and proliferation. In vivo, overstabilization of HIF1, either genetically or by exposure to systemic hypoxia, reduces AβAM clustering and proliferation and increases Aβ neuropathology. In the human AD hippocampus, upregulation of HIF1α and HIF1 target genes correlates with reduced Aβ plaque microglial coverage and an increase of Aβ plaque-associated neuropathology. Thus, hypoxia (a modifiable AD risk factor) hijacks microglial mitochondrial metabolism and converges with genetic susceptibility to cause AD microglial dysfunction.Instituto de Salud Carlos III CD09/0007, PI18/01556, PI18/01557Ministerio de Educación, Cultura y Deporte FPU14/02115, AP2010‐1598, FPU16/02050, FPU15/02898, BES-2010-033886Ministerio de Economia, Industria y Competitividad SAF2012‐33816, SAF2015‐64111‐R, SAF2017-90794-REDT, PIE13/0004, BFU2016-76872-R, BES-2011-047721Junta de Andalucía P12‐CTS‐2138, P12‐CTS‐2232, UMA18-FEDERJA-211, US‐126273

Systemic and Local Hypoxia Synergize Through HIF1 to Compromise the Mitochondrial Metabolism of Alzheimer's Disease Microglia

Microglial cells are key contributors to Alzheimer’s disease (AD), constituting the first cellular line against Aß plaques. Local hypoxia and hypoperfusion, which are typically present in peripheral inflammatory foci, are also common in the AD brain. We describe here that Aß deposits are hypoxic and hypoperfused and that Aß plaque-associated microglia (AßAM) are characterized by the expression of hypoxia-inducible factor 1 (HIF1)-regulated genes. Notably, AßAM simultaneously upregulate the expression of genes involved in anaerobic glycolysis and oxidative mitochondrial metabolism, show elongated mitochondria surrounded by rough endoplasmic reticulum, and blunt the HIF1-mediated exclusion of pyruvate from the mitochondria through the pyruvate dehydrogenase kinase 1 (PDK1). Overstabilization of HIF1 –by genetic (von Hippel-Lindau deficient microglia) or systemic hypoxia (an AD risk factor)– induces PDK1 in microglia and reduces microglial clustering in AD mouse models. The human AD brain exhibits increased HIF1 activity and a hypoxic brain area shows reduced microglial clustering. The loss of the microglial barrier associates with augmented Aß neuropathology both in the chronic hypoxia AD mouse model and the human AD brain. Thus, the synergy between local and systemic AD risk factors converges with genetic susceptibility to cause microglial dysfunction.Peer reviewe

Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1

Genetic Alzheimer’s disease (AD) risk factors associate with reduced defensive amyloid β plaque-associated microglia (AβAM), but the contribution of modifiable AD risk factors to microglial dysfunction is unknown. In AD mouse models, we observe concomitant activation of the hypoxia-inducible factor 1 (HIF1) pathway and transcription of mitochondrial-related genes in AβAM, and elongation of mitochondria, a cellular response to maintain aerobic respiration under low nutrient and oxygen conditions. Overactivation of HIF1 induces microglial quiescence in cellulo, with lower mitochondrial respiration and proliferation. In vivo, overstabilization of HIF1, either genetically or by exposure to systemic hypoxia, reduces AβAM clustering and proliferation and increases Aβ neuropathology. In the human AD hippocampus, upregulation of HIF1α and HIF1 target genes correlates with reduced Aβ plaque microglial coverage and an increase of Aβ plaque-associated neuropathology. Thus, hypoxia (a modifiable AD risk factor) hijacks microglial mitochondrial metabolism and converges with genetic susceptibility to cause AD microglial dysfunction.R.M.-D. was the recipient of a Sara Borrell fellowship from Instituto de Salud Carlos III (ISCIII) (CD09/0007). N.L.-U., C.O.-d.S.L., C.R.-M. and M.I.A.-V. were the recipients of FPU fellowships from Spanish Ministry of Education, Culture and Sport (FPU14/02115, AP2010‐1598, FPU16/02050 and FPU15/02898, respectively). A.H.-G. was the recipient of an FPI fellowship from the Spanish Ministry of Education, Culture and Sport (BES-2010-033886). This work was supported by grants from the Spanish MINEICO, ISCIII and FEDER (European Union) (SAF2012‐33816, SAF2015‐64111‐R, SAF2017-90794-REDT and PIE13/0004 to A.P.); by the Regional Government of Andalusia co-funded by CEC and FEDER funds (European Union) (‘Proyectos de Excelencia’; P12‐CTS‐2138 and P12‐CTS‐2232 to A.P.); by the ‘Ayuda de Biomedicina 2018’, Fundación Domingo Martínez (to A.P.) ; by the ISCIII of Spain, co-financed by FEDER funds (European Union) through grants PI18/01556 (to J.V.) and PI18/01557 (to A. Gutierrez); by Junta de Andalucía, co-financed by FEDER funds (grants UMA18-FEDERJA-211 (to A. Gutierrez) and US‐1262734 (to J.V.)); and by Spanish MINEICO (BFU2016-76872-R and BES-2011-047721 to E.B.).Peer reviewe

Perfil de los pacientes que acuden al médico internista para valoración de osteoporosis: registro OSTEOMED

Producción CientíficaAntecedentes y objetivo: La osteoporosis se considera un trastorno generalizado del esqueleto en el que existe una alteración de la resistencia ósea que predispone a la persona a un mayor riesgo de fractura. Este estudio transversal pretende recoger y presentar las principales características clínicas de los pacientes que acuden a la consulta de los médicos internistas en Espa˜na. Conocer estas características podría facilitar la puesta en marcha de planes de actuación para mejorar la atención de estos pacientes de manera más eficaz y eficiente. Material y métodos: A través del análisis del registro OSTEOMED (Osteoporosis en Medicina Interna), este trabajo presenta las principales características clínicas de los pacientes con osteoporosis que acudieron a las consultas de Medicina Interna en 23 centros hospitalarios espa˜noles entre 2012 y 2017. Se han analizado los motivos de consulta, los valores densitométricos, la presencia de comorbilidades, el tratamiento prescrito y otros factores relacionados con el estilo de vida. Resultados: En total se evaluó a 2.024 pacientes con osteoporosis (89,87% mujeres, 10,13% hombres). La edad media de los pacientes fue de 64,1 ± 12,1 a˜nos (mujeres, 64,7 ± 11,5 a˜nos; hombres, 61,2 ± 14,2 a˜nos). No hubo diferencia entre sexos en la historia de caídas recientes (9,1-6,7%), mientras que sí se apreció en la ingesta diaria de calcio de lácteos (553,8 ± 332,6 mg en mujeres vs. 450,2 ± 303,3 mg en hombres; p < 0,001) y en causas secundarias de osteoporosis(13% de hombres vs. 6,5% de mujeres; p < 0,001). En la muestra se observaron un total de 404fracturas (20%), destacando el número de fracturas vertebrales confirmadas (17,2%, 35,6% enhombres vs. 15,2% de las mujeres; p < 0,001). Una gran parte de los pacientes no recibía eltratamiento indicado y presentaba bajos niveles de actividad física y exposición solar. Un por-centaje importante de pacientes presentó comorbilidades asociadas, siendo las más frecuentesla hipertensión (32%) y la dislipidemia (28%).Conclusiones: Estos resultados definen el perfil del paciente con osteoporosis que acude a laconsulta de Medicina Interna en Espa˜na. Además, ponen de manifiesto el carácter multisistémicode esta entidad que junto con su elevada prevalencia determinan que las consultas específicasde Medicina Interna dedicadas a su manejo son el lugar adecuado para la atención de estos pacientes

Altimetry for the future: Building on 25 years of progress

In 2018 we celebrated 25 years of development of radar altimetry, and the progress achieved by this methodology in the fields of global and coastal oceanography, hydrology, geodesy and cryospheric sciences. Many symbolic major events have celebrated these developments, e.g., in Venice, Italy, the 15th (2006) and 20th (2012) years of progress and more recently, in 2018, in Ponta Delgada, Portugal, 25 Years of Progress in Radar Altimetry. On this latter occasion it was decided to collect contributions of scientists, engineers and managers involved in the worldwide altimetry community to depict the state of altimetry and propose recommendations for the altimetry of the future. This paper summarizes contributions and recommendations that were collected and provides guidance for future mission design, research activities, and sustainable operational radar altimetry data exploitation. Recommendations provided are fundamental for optimizing further scientific and operational advances of oceanographic observations by altimetry, including requirements for spatial and temporal resolution of altimetric measurements, their accuracy and continuity. There are also new challenges and new openings mentioned in the paper that are particularly crucial for observations at higher latitudes, for coastal oceanography, for cryospheric studies and for hydrology. The paper starts with a general introduction followed by a section on Earth System Science including Ocean Dynamics, Sea Level, the Coastal Ocean, Hydrology, the Cryosphere and Polar Oceans and the ‘‘Green” Ocean, extending the frontier from biogeochemistry to marine ecology. Applications are described in a subsequent section, which covers Operational Oceanography, Weather, Hurricane Wave and Wind Forecasting, Climate projection. Instruments’ development and satellite missions’ evolutions are described in a fourth section. A fifth section covers the key observations that altimeters provide and their potential complements, from other Earth observation measurements to in situ data. Section 6 identifies the data and methods and provides some accuracy and resolution requirements for the wet tropospheric correction, the orbit and other geodetic requirements, the Mean Sea Surface, Geoid and Mean Dynamic Topography, Calibration and Validation, data accuracy, data access and handling (including the DUACS system). Section 7 brings a transversal view on scales, integration, artificial intelligence, and capacity building (education and training). Section 8 reviews the programmatic issues followed by a conclusion

Altimetry for the future: building on 25 years of progress

In 2018 we celebrated 25 years of development of radar altimetry, and the progress achieved by this methodology in the fields of global and coastal oceanography, hydrology, geodesy and cryospheric sciences. Many symbolic major events have celebrated these developments, e.g., in Venice, Italy, the 15th (2006) and 20th (2012) years of progress and more recently, in 2018, in Ponta Delgada, Portugal, 25 Years of Progress in Radar Altimetry. On this latter occasion it was decided to collect contributions of scientists, engineers and managers involved in the worldwide altimetry community to depict the state of altimetry and propose recommendations for the altimetry of the future. This paper summarizes contributions and recommendations that were collected and provides guidance for future mission design, research activities, and sustainable operational radar altimetry data exploitation. Recommendations provided are fundamental for optimizing further scientific and operational advances of oceanographic observations by altimetry, including requirements for spatial and temporal resolution of altimetric measurements, their accuracy and continuity. There are also new challenges and new openings mentioned in the paper that are particularly crucial for observations at higher latitudes, for coastal oceanography, for cryospheric studies and for hydrology. The paper starts with a general introduction followed by a section on Earth System Science including Ocean Dynamics, Sea Level, the Coastal Ocean, Hydrology, the Cryosphere and Polar Oceans and the “Green” Ocean, extending the frontier from biogeochemistry to marine ecology. Applications are described in a subsequent section, which covers Operational Oceanography, Weather, Hurricane Wave and Wind Forecasting, Climate projection. Instruments’ development and satellite missions’ evolutions are described in a fourth section. A fifth section covers the key observations that altimeters provide and their potential complements, from other Earth observation measurements to in situ data. Section 6 identifies the data and methods and provides some accuracy and resolution requirements for the wet tropospheric correction, the orbit and other geodetic requirements, the Mean Sea Surface, Geoid and Mean Dynamic Topography, Calibration and Validation, data accuracy, data access and handling (including the DUACS system). Section 7 brings a transversal view on scales, integration, artificial intelligence, and capacity building (education and training). Section 8 reviews the programmatic issues followed by a conclusion

Diseño de un sistema de información geográfica para un desarrollo sustentable.

A través del desarrollo de este proyecto se busca aplicar y alcanzar las premisas básicas que giran en torno al desarrollo sustentable, con base en la aplicación de eco-tecnologías que permiten la disminución del impacto ambiental generado por los usuarios (huéspedes) sobre el ecosistema aledaño a la zona donde se localizan las villas eco-turísticas "La Joya"