Peripheral myeloid cells infiltrate the hippocampus of Alzheimer's disease patients.

Microglia, the brain-resident myeloid cells, play a major role in the immune responses of the nervous system and in the pathogenesis of Alzheimer's disease (AD). However, the presence of peripheral myeloid cells in the AD brains remain to be demonstrated. Cellular and molecular approaches have been carried out in post-mortem hippocampal samples from patients with AD and age-matched controls without neurological symptoms. Our study provides evidence that circulating monocytes infiltrate the AD brains. Our findings showed that a high proportion of demented cases was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes-derived cells (MDC), among which stands the scavenger receptor Cd163. These Cd163-positive MDC invaded the brain parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. These cells infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. Besides, control individuals with high amyloid pathology, showed no signs of MDC brain infiltration or plaque invasion. The MDC infiltration was associated with the progression and severity of AD pathology.These results reveal the co-existence of distinct myeloid populations associated with amyloid plaques during disease progression, as well their region-specific contribution to neuroimmune protection. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only to microglia, but also to peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying AD progression.Supported by ISCiii grants(PI21-0915(AG),PI21-00914(JV)co-financed by FEDER funds from European Union;Junta de Andalucia grants P18-RT-2233(AG) and US-1262734(JV)co-financed by Programa Operativo FEDER 2014-2020;PPIT.UMA.B1-2019-07(ESM). Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Microglia in Alzheimer’s Disease: Activated, Dysfunctional or Degenerative

Microglial activation has been considered a crucial player in the pathological process of multiple human neurodegenerative diseases. In some of these pathologies, such as Amyotrophic Lateral Sclerosis or Multiple Sclerosis, the immune system and microglial cells (as part of the cerebral immunity) play a central role. In other degenerative processes, such as Alzheimer’s disease (AD), the role of microglia is far to be elucidated. In this “mini-review” article, we briefly highlight our recent data comparing the microglial response between amyloidogenic transgenic models, such as APP/PS1 and AD patients. Since the AD pathology could display regional heterogeneity, we focus our work at the hippocampal formation. In APP based models a prominent microglial response is triggered around amyloid-beta (Aβ) plaques. These strongly activated microglial cells could drive the AD pathology and, in consequence, could be implicated in the neurodegenerative process observed in models. On the contrary, the microglial response in human samples is, at least, partial or attenuated. This patent difference could simply reflect the lower and probably slower Aβ production observed in human hippocampal samples, in comparison with models, or could reflect the consequence of a chronic long-standing microglial activation. Beside this differential response, we also observed microglial degeneration in Braak V–VI individuals that, indeed, could compromise their normal role of surveying the brain environment and respond to the damage. This microglial degeneration, particularly relevant at the dentate gyrus, might be mediated by the accumulation of toxic soluble phospho-tau species. The consequences of this probably deficient immunological protection, observed in AD patients, are unknown.España, Instituto de Salud Carlos III PI15/00957, PI15/00796España Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucia Proyecto de Excelencia CTS-203

Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus

Background: Axonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in Alzheimer’s patients and transgenic models at early ages. These axonal dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. It has been also proposed that dystrophies might interfere with normal intracellular proteolysis. In this work, we have investigated the progression of the hippocampal pathology and the possible implication in Abeta production in young (6 months) and aged (18 months) PS1(M146L)/APP(751sl) transgenic mice. Results: Our data demonstrated the existence of a progressive, age-dependent, formation of axonal dystrophies, mainly located in contact with congophilic Abeta deposition, which exhibited tau and neurofilament hyperphosphorylation. This progressive pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we also observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition of these lysosomal proteases at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. We have also investigated the repercussion of these deficiencies on the APP metabolism. Our data demonstrated the existence of an increase in the amyloidogenic pathway, which was reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in BACE and gamma-secretase activities. In vitro experiments, using APPswe transfected N2a cells, demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data also demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes. Conclusion: A progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and, in minor extent, proteasomal activity could be directly implicated in the progressive accumulation of APP derived fragments (and Abeta peptides) in parallel with the increase of BACE-1 and gamma-secretase activities. This retard in the APP metabolism seemed to be directly implicated in the synaptic Abeta accumulation and, in consequence, in the pathology progression between synaptically connected regions

Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus

Dystrophic neurites associated with amyloid plaques precede neuronal death and manifest early in Alzheimer’s disease (AD). In this work we have characterized the plaque-associated neuritic pathology in the hippocampus of young (4- to 6-month-old) PS1M146L/ APP751SL mice model, as the initial degenerative process underlying functional disturbance prior to neuronal loss. Neuritic plaques accounted for almost all fibrillar deposits and an axonal origin of the dystrophies was demonstrated. The early induction of autophagy pathology was evidenced by increased protein levels of the autophagosome marker LC3 that was localized in the axonal dystrophies, and by electron microscopic identification of numerous autophagic vesicles filling and causing the axonal swellings. Early neuritic cytoskeletal defects determined by the presence of phosphorylated tau (AT8-positive) and actin–cofilin rods along with decreased levels of kinesin-1 and dynein motor proteins could be responsible for this extensive vesicle accumulation within dystrophic neurites. Although microsomal Ab oligomers were identified, the presence of A11-immunopositive Ab plaques also suggested a direct role of plaque-associated Ab oligomers in defective axonal transport and disease progression. Most importantly, presynaptic terminals morphologically disrupted by abnormal autophagic vesicle buildup were identified ultrastructurally and further supported by synaptosome isolation. Finally, these early abnormalities in axonal and presynaptic structures might represent the morphological substrate of hippocampal dysfunction preceding synaptic and neuronal loss and could significantly contribute to AD pathology in the preclinical stages.Fondo de Investigación Sanitaria (FIS). Instituto de Salud Carlos III, España. PS09/00099, PS09/00151, PS09/00848 y PS09/00376Junta de Andalucía. SAS P09/496 y CTS-479

Monocyte-derived cells invade amyloid plaques in human alzheimer’s disease hippocampus.

Microglia, the brain-resident myeloid cells, play a major role in the immune responses of the nervous system and in the pathogenesis of Alzheimer's disease (AD). However, the presence of peripheral myeloid cells in the AD brains, and their contribution to disease progression, remain to be demonstrated. In this work, cellular and molecular approaches have been carried out in post-mortem hippocampal samples from patients with dementia (Braak V-VI) and age-matched asymptomatic cases (Braak II). Our study provides evidence that circulating monocytes infiltrate the AD brains. Our findings showed that a high proportion of demented individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes-derived cells (MDC), among which stands the scavenger receptor Cd163. These Cd163-positive MDC invaded the brain parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. These cells infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. Besides, asymptomatic individuals with high amyloid pathology, showed no signs of MDC brain infiltration or plaque invasion. The MDC infiltration was associated with the progression and severity of AD pathology. These results reveal the co-existence of distinct myeloid populations associated with amyloid plaques during disease progression, as well their region-specific contribution to neuroimmune protection. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only to microglia, but also to peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying AD progression.Supported by ISCiii grants (PI21-0915 (to AG),PI21-00914 (to JV) co-financed by FEDER funds from European Union, by Junta de Andalucia grants P18-RT-2233 (to AG) and US-1262734 (to JV) co-financed by Programa Operativo FEDER 2014-2020, and by grant PPIT.UMA.B1-2019-07 (to ESM). Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Monocyte-derived Cells Invade Brain Parenchyma and Amyloid Plaques in Human Alzheimer’s Disease Hippocampus

Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of the CNS and the pathogenesis of Alzheimer's disease (AD). However, the contribution of nonparenchymal or brain-infiltrated myeloid cells to disease progression remains to be demonstrated. Here, we show that monocyte-derived cells (MDC) invade brain parenchyma in advanced stages of AD continuum using transcriptional analysis and immunohistochemical characterization in post-mortem human hippocampus. Our findings demonstrated that a high proportion (60%) of demented Braak V–VI individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes, among which stands the membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes or Cd163. These Cd163-positive MDC invaded the hippocampal parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. Moreover, and most interesting, these invading monocytes infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. However, in aged-matched control individuals with hippocampal amyloid pathology, no signs of MDC brain infiltration or plaque invasion were found. The previously reported microglial degeneration/dysfunction in AD hippocampus could be a key pathological factor inducing MDC recruitment. Our data suggest a clear association between MDC infiltration and endothelial activation which in turn may contribute to damage of the blood brain barrier integrity. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only for microglia but also for the peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying the progression of AD.European Commission. Fondo Europeo de Desarrollo Regional PI18/01556, PI21/00914, PI18/01557, PI21/00915Junta de Andalucía US-1262734, P20-00843, UMA18-FEDERJA-211, PI18-RT-2233Universidad de Málaga B-2019_06Ministerio de Ciencia, Innovación y Universidades RYC-2017-2187

Amyloid‐β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease

Reactive astrocytes and dystrophic neurites, most aberrant presynaptic elements, are found surrounding amyloid‐β plaques in Alzheimer's disease (AD). We have previously shown that reactive astrocytes enwrap, phagocytose, and degrade dystrophic synapses in the hippocampus of APP mice and AD patients, but affecting less than 7% of dystrophic neurites, suggesting reduced phagocytic capacity of astrocytes in AD. Here, we aimed to gain insight into the underlying mechanisms by analyzing the capacity of primary astrocyte cultures to phagocytose and degrade isolated synapses (synaptoneurosomes, SNs) from APP (containing dystrophic synapses and amyloid‐β peptides), Tau (containing AT8‐ and AT100‐positive phosphorylated Tau) and WT (controls) mice. We found highly reduced phagocytic and degradative capacity of SNs‐APP, but not AT8/AT100‐positive SNs‐Tau, as compared with SNs‐WT. The reduced astrocyte phagocytic capacity was verified in hippocampus from 12‐month‐old APP mice, since only 1.60 ± 3.81% of peri‐plaque astrocytes presented phagocytic structures. This low phagocytic capacity did not depend on microglia‐mediated astrocyte reactivity, because removal of microglia from the primary astrocyte cultures abrogated the expression of microglia‐dependent genes in astrocytes, but did not affect the phagocytic impairment induced by oligomeric amyloid‐β alone. Taken together, our data suggest that amyloid‐β, but not hyperphosphorylated Tau, directly impairs the capacity of astrocytes to clear the pathological accumulation of oligomeric amyloid‐β, as well as of peri‐plaque dystrophic synapses containing amyloid‐β, perhaps by reducing the expression of phagocytosis receptors such as Mertk and Megf10, thus increasing neuronal damage in AD. Therefore, the potentiation or recovery of astrocytic phagocytosis may be a novel therapeutic avenue in AD.Research funding: Centro de Invesitgacion Biomedica en Red Enfermedades Neurodegenetativas (CIBERNED). Grant Numbers: CB06/05/0094, CB06/05/1116; Instituto de Salud Carlos III co‐financed by FEDER funds from European Union. Grant Numbers: PI18/01556, PI18/01557; Junta de Andalucia Consejería de Economía y Conocimiento co‐financed by Programa Operativo FEDER 2014‐2020. Grant Numbers: PY18‐RT‐2233, UMA18‐FEDERJA‐211, US‐1262734; La Marató‐TV3 Foundation. Grant Numbers: 20141430, 20141431, 20141432

Educando de otras maneras. Hijos de la tierra : rompe tu silencio

El trabajo obtuvo un premio de la Modalidad B de los Premios Tomás García Verdejo a las buenas prácticas educativas en la Comunidad Autónoma de Extremadura para el curso 2011/2012Se presenta un proyecto que pretende enseñar valores y fomentar el gusto por la lectura con el soporte de las nuevas tecnologías. Se describe la Jornada interdisciplinar 'Hijos de la tierra: rompe tu silencio' que consistió en realizar actividades y talleres relacionados con los temas transversales trabajados a lo largo del curso desde las distintas asignaturas y desde actividades generadas desde la biblioteca del centro, aunque tuvieron como tema central el medioambiente y el fomento de valores como la solidaridad, el respeto, la tolerancia, etcExtremaduraES

Mirando a África

Este proyecto pretende acercar a la comunidad educativa del centro una realidad tan próxima, compleja y dramática como la del continente africano, desde casi todas las materias. Y pretende hacerlo en coherencia con valores que identifican al centro. Los objetivos son fomentar la colaboración y participación de los alumnos intercambiando sus propias experiencias; potenciar una conciencia social y ecológica; formar integralmente a los alumnos para el mejor desarrollo de la sociedad; valorar la utilidad de la enseñanza activa y el aprendizaje cooperativo; diseñar actividades que permitan desarrollar una enseñanza interdisciplinar; posibilitar que los alumnos desarrollen estrategias globalizadoras de organización del conocimiento mediante el tratamiento de la información; favorecer el aprendizaje significativo; animar al profesorado a buscar estrategias que favorezcan la actividad didáctica; fomentar la lectura y el uso correcto de la expresión oral y escrita, además de mejorar la ortografía; extender el conocimiento y la utilización de las nuevas tecnologías de la información y la comunicación; estrechar las relaciones entre los diferentes sectores de la comunidad educativa; fomentar la participación activa en la vida social; mejorar la convivencia en el centro; desarrollar hábitos de vida saludables; provocar en los alumnos una visión positiva del centro como lugar de ocio y de enriquecimiento cultural; desarrollar y favorecer las inquietudes culturales de los alumnos; desarrollar las actitudes positivas hacia otras culturas; extender el conocimiento de lenguas extranjeras y mantener relaciones estables de colaboración con instituciones culturales y sociales. Las actividades desarrolladas se organizan en tres modalidades que son actividades globales que implican a toda la comunidad educativa como un concurso de lectura llamado África desde la biblioteca, el día del Libro, viaje de fin de curso a Túnez, apadrinar una escuela en Marruecos, una jornada cultural antes de las vacaciones de Semana Santa, talleres a cargo de la Fundación Yehudi Menuhin y Hora 31 con ciclos de charlas y conferencias; actividades durante el horario lectivo en los distintos departamentos didácticos como proyecciones de películas, composición de textos, debates y trabajos en equipo; y las actividades realizadas fuera del horario lectivo como son talleres, cineclub, coloquios, exposiciones, actividades de cooperación y asistir a diversos espectáculos. La metodología es diversa, en relación con la pluralidad de actividades que se llevan a cabo. Como indicadores del proceso de evaluación se toman para las actividades del currículo, la propia evaluación de profesores. Aunque es un indicador cuantitativo para el análisis final y junto a otros parámetros, se trabaja también la evaluación cualitativa, para que las conclusiones tengan un carácter más global de los resultados del proyecto. Por el contrario, las actividades que se realizan fuera del horario lectivo se miden con el grado de participación. Además como herramienta de evaluación individual se elaboran encuestas para alumnos y profesores para que reflejen sus opiniones personales sobre el proyecto. Se adjunta como anexo dos CD-ROM y cuestionarios..Madrid (Comunidad Autónoma). Consejería de Educación. Dirección General de Mejora de la Calidad de la EnseñanzaMadridMadrid (Comunidad Autónoma). Subdirección General de Formación del Profesorado. CRIF Las Acacias; General Ricardos 179 - 28025 Madrid; Tel. + 34915250893ES

La evaluación colegiada de las competencias básicas en la Comunidad Autónoma de Canarias : hacia un modelo de escuela inclusiva y sostenible

Precede al título: Educación Primaria y Educación Secundaria ObligatoriaLa Ley Orgánica de Educación (LOE) introduce el concepto de «competencias básicas» como eje articulador del currículo, conectando de pleno con las reflexiones y las estrategias que se están desarrollando en otros sistemas educativos internacionales a la luz del informe Delors (1996), el documento DeSeCo (Definición y Selección de Competencias fundamentales) elaborado por la OCDE, de las evaluaciones PISA (Programa para la Evaluación Internacional del Alumnado), etc. Esta propuesta centra el foco en la dimensión formativa de la «evaluación», aspecto inacabado con la LOGSE (Ley Orgánica General del Sistema Educativo), a pesar de los esfuerzos realizados en esa dirección. Trabajar en las aulas para la consecución de las «competencias básicas» lleva ineludiblemente al problema de cómo evaluarlas de forma colegiada —cuando la propia ordenación del sistema educativo fragmenta cada una de las enseñanzas en diferentes áreas o materias— y de cómo emplear la información que proporciona esta labor para hacer valer el sentido formativo y regulador que debe tener la evaluación de las competencias básicas.Consejería de Educación y Universidades. Dirección General de Ordenación, Innovación y Promoción Educativa; Avda. Buenos Aires, 5; 38071 Tenerife; Tel. +34922592592; Fax +34922592570; [email protected]