Aproximación neuropatológica a la fisiopatología de la enfermedad de Alzheimer

Tesis descargada de TESEOIntroduction: Amyloid plaques and neurofibrillary tangles (NFTs) are the pathological hallmarks of Alzheimer disease (AD), but other important lesions are cerebral amyloid angiopathy, glial responses (reactive astrocytes and activated microglia), and a progressive loss of synapses and neurons. The most widely accepted hypothesis on the pathophysiology of AD, termed ¿amyloid cascade hypothesis¿, postulates that amyloid deposition triggers a cascade of adverse events that include, among others, glial responses, tau hyperphosphorylation and aggregation in NFTs, and massive synaptic and neuron losses, that ultimately lead to dementia. Rationale/hypothesis/aims: We hypothesized that as the disease advances the amyloid cascade becomes progressively independent of its initiator, the Aß peptide, so that removing the plaques from the brain in the symptomatic phase would be insufficient to arrest or rescue Aß downstream effects. We aimed at 1) understanding the progression of the different pathological lesions over the course of the disease and their relationships; and 2) testing whether the clearance of amyloid plaques from the human AD brain by anti-Aß immunization can arrest this pathogenic cascade. Subjects/methods: We performed postmortem studies using immunohistochemistry and stereology-based quantitative methods on paraffin sections of the hippocampus and temporal associative neocortex of AD patients (including 5 participants in the Phase 2a trial of anti-Aß active immunization AN1792, by Elan Pharmaceuticals Inc.). Results: Amyloid deposition in the temporal cortex plateaus early after symptom onset, whereas glial responses increase linearly over the clinical course of the disease and parallel the accumulation of NFTs and the progression of cortical atrophy. The increased glial responses occurs mainly in the proximity of dense-core plaques but also in the proximity of NFTs, suggesting a progressive independence from the plaques. Plaque clearance by anti-Aß active immunization in patients with mild-to-moderate AD is associated with subtle improvements in neurite trajectories and tau hyperphosphorylation, but does not rescue tau misfolding/aggregation in NFTs. Discussion/conclusions: these results support the existence of an amyloid-dependent and an amyloid-independent stages of AD pathophysiology. Amyloid burden remains essentially constant throughout the clinical course of the disease, consistent with the vast majority of amyloid deposition preceding clinical onset (amyloid-dependent stage). By contrast, glial responses increase in parallel to the clinical course, the accumulation of NFTs, and the cortical atrophy, suggesting that they become progressively independent from plaques. Moreover, NFTs persist after plaque clearance upon anti-Aß immunization, confirming that neurodegenerative phenomena become independent of Aß (amyloid-independent stage).Premio Extraordinario de Doctorado U

Photoacoustic effect measurement in aqueous suspensions of gold nanorods caused by low-frequency and low-power near-infrared pulsing laser irradiation

When aqueous suspensions of gold nanorods are irradiated with a pulsing laser (808 nm), pressure waves appear even at low frequencies (pulse repetition rate of 25 kHz). We found that the pressure wave amplitude depends on the dynamics of the phenomenon. For fixed concentration and average laser current intensity, the amplitude of the pressure waves shows a trend of increasing with the pulse slope and the pulse maximum amplitude.We postulate that the detected ultrasonic pressure waves are a sort of shock waves that would be generated at the beginning of each pulse, because the pressure wave amplitude would be the result of the positive interference of all the individual shock waves

Aproximación al pensamiento crítico de la visión Taylorista: Caso fábrica Imbabura. //Approach to the critical thinking of the Taylorist vision: Imbabura factory case.

El objetivo de este estudio es presentar perspectivas teóricas antagónicas del Taylorismo y su aplicación en la que otrora fue el ícono de la producción textil de la provincia de Imbabura en Ecuador.  En este contexto, la investigación busca conectar los momentos históricos, sociales y productivos de la dinámica organizacional de la Fábrica Imbabura con la teoría de la administración científica taylorista. Este estudio se destaca por la ambivalencia teórica que se pone de manifiesto entre articulación de posiciones a favor y en contra del taylorismo, consecuentemente esta confrontación posicional produce un ejercicio de reflexión crítica en el contexto espacial de la Fábrica Imbabura. Para articular el estudio se recurrió a una revisión de literatura sobre Administración Científica centrada en el Taylorismo, en artículos revisado por pares en las bases de datos Web of Science y DOAJ. Además, se recurrió a fuentes adicionales de información, como literatura gris y libros de texto para obtener más elementos que pueda nutrir el ensayo. La contribución del ensayo se refleja un aporte al campo de la perspectiva del pensamiento crítico del taylorismo en el contexto de un caso en particular. AbstractThe objective of this study is to present antagonistic theoretical perspectives of Taylorism and its application in what was once the icon of textile production in the province of Imbabura in Ecuador. In this context, the research seeks to connect the historical, social and productive moments of the organizational dynamics of the Imbabura Factory with the theory of Taylorist scientific administration. This study is highlighted by the theoretical ambivalence that is evident between articulation of positions in favor and against Taylorism, consequently this positional confrontation produces an exercise of critical reflection in the spatial context of the Imbabura Factory. To articulate the study, a review of the Scientific Administration literature focused on Taylorism, in peer-reviewed articles in the databases of Web of Science and DOAJ, was used. In addition, additional sources of information were used, such as gray literature and textbooks to obtain more elements that could support the essay. The contribution of the essay reflects a contribution to the field of perspective of the critical thinking of Taylorism in the context of a particular case

Evaluación de un panel de microsatélites para el control de filiación en razas caprinas españolas de aptitud cárnica

Hemos evaluado el potencial de 20 microsatélites para la realización de los controles de filiación (paternidad y/o maternidad) de las razas caprinas españolas de aptitud cárnica. En base a sus condi- ciones técnicas hemos seleccionado nueve para este fin para poder compatibilizar la eficiencia con el coste económico. La mayor parte de los marcadores son de origen bovino. De los marcadores seleccio- nados se han calculado los valores del Contenido de Información Polimórfica (PIC), y las probabilida- des de exclusión (PE), por marcador y conjuntas, de un progenitor falso dado como verdadero a partir de las frecuencias alélicas de 30 individuos no emparentados de cada una de las 6 razas caprinas espa- ñolas de aptitud cárnica estudiadas (un total de 180 individuos): Moncaína, Blanca Andaluza, Negra Serrana, Blanca Celtibérica, Pirenaica y Azpi Gorri. Todos los marcadores seleccionados han sido infor- mativos en estas razas. La probabilidad de exclusión conjunta cuando solo un progenitor es conocido ha oscilado entre el 96,4 % en la raza Moncaína y 98,9 % en la raza Blanca Celtibérica siendo en todos las razas superior al 99% cuando se conocen los dos progenitores y queremos testar si la descendencia está asignada correctamente.Assessment of a microsatellite marker set for parentage testing in six Spanish goat breeds We have analysed 20 microsatellite markers on six Spanish goat populations bred for meat produc- tion. Nine loci were selected for parentage testing due to technical reasons. Polymorphic Informative Content (PIC) and parentage exclusion probabilities per marker and for the whole marker set were computed on allele frequencies from a total of 180 unrelated individuals (30 per breed) belonging to six Spanish goat breeds: Moncaína, Blanca Andaluza, Negra Serrana, Blanca Celtibérica, Pirenaica and Azpi Gorri. The nine markers selected were informative. In order to quantify the usefulness of the microsatellite set for parentage testing, we calculated exclusion probabilities for the two most likely scenarios: a) combined probability of exclusion of a parent when the other is known; and b) combined probability of exclusion when both parent are known and one of them is false. The exclusion proba- bility for the scenario a) varied from 96.4 % (Moncaína breed) to 98,9 % (Blanca Celtibérica breed); the exclusion probabilities for the scenario b) were always higher than 99%Ministerio de Educación y Ciencia RZ01-010-

Cyclic multiplex fluorescent immunohistochemistry and machine learning reveal distinct states of astrocytes and microglia in normal aging and Alzheimer’s disease

Background Astrocytes and microglia react to Aβ plaques, neurofibrillary tangles, and neurodegeneration in the Alzheimer’s disease (AD) brain. Single-nuclei and single-cell RNA-seq have revealed multiple states or subpopulations of these glial cells but lack spatial information. We have developed a methodology of cyclic multiplex fluorescent immunohistochemistry on human postmortem brains and image analysis that enables a comprehensive morphological quantitative characterization of astrocytes and microglia in the context of their spatial relationships with plaques and tangles. Methods Single FFPE sections from the temporal association cortex of control and AD subjects were subjected to 8 cycles of multiplex fluorescent immunohistochemistry, including 7 astroglial, 6 microglial, 1 neuronal, Aβ, and phospho-tau markers. Our analysis pipeline consisted of: (1) image alignment across cycles; (2) background subtraction; (3) manual annotation of 5172 ALDH1L1+ astrocytic and 6226 IBA1+ microglial profiles; (4) local thresholding and segmentation of profiles; (5) machine learning on marker intensity data; and (6) deep learning on image features. Results Spectral clustering identified three phenotypes of astrocytes and microglia, which we termed “homeostatic,” “intermediate,” and “reactive.” Reactive and, to a lesser extent, intermediate astrocytes and microglia were closely associated with AD pathology (≤ 50 µm). Compared to homeostatic, reactive astrocytes contained substantially higher GFAP and YKL-40, modestly elevated vimentin and TSPO as well as EAAT1, and reduced GS. Intermediate astrocytes had markedly increased EAAT2, moderately increased GS, and intermediate GFAP and YKL-40 levels. Relative to homeostatic, reactive microglia showed increased expression of all markers (CD68, ferritin, MHC2, TMEM119, TSPO), whereas intermediate microglia exhibited increased ferritin and TMEM119 as well as intermediate CD68 levels. Machine learning models applied on either high-plex signal intensity data (gradient boosting machines) or directly on image features (convolutional neural networks) accurately discriminated control vs. AD diagnoses at the single-cell level. Conclusions Cyclic multiplex fluorescent immunohistochemistry combined with machine learning models holds promise to advance our understanding of the complexity and heterogeneity of glial responses as well as inform transcriptomics studies. Three distinct phenotypes emerged with our combination of markers, thus expanding the classic binary “homeostatic vs. reactive” classification to a third state, which could represent “transitional” or “resilient” glia.España Ministry of Science, Innovation, and Universities FPU fellowship to CM-CMassachusetts Alzheimer’s Disease Research Center grant P30AG062421 to BTH, and 1R56AG061196 to BTHAlzheimer’s Association (AACF17-524184 and AACF-17-524184-RAPID to AS-P

Social Pedagogy and school pedagogy for peace construction in educational institutions and vulnerable communities in Colombian Caribbean Region

El propósito de la investigación es analizar el fenómeno de la conflictividad escolar y comunitaria en la región caribe colombiana para la construcción de cultura de paz. La metodología utilizada es mixta (multimétodo) con una muestra de 344 docentes y comunidad educativa que fueron encuestadas (Análisis SPSS), complementada con 35 entrevistas a familias y agentes sociales y 7 grupos de discusión (Análisis NVIVO). Los resultados y la discusión plantean un análisis descriptivo vinculado con las necesidades percibidas y situaciones más problemáticas, que corresponden a dos tipos de entornos: 1) comunidad social: Aparece en primer lugar el desempleo, seguido de los diversos tipos de violencias (directas, estructurales y culturales); y por último, la falta de cobertura social (servicios básicos de atención social cubiertos por la Alcaldía y/o Gobernación: atención de servicios sociales, vivienda, suministros, etc.); 2) comunidad educativa: que aparece, en primer lugar la necesidad de mediación social de las escuelas con las familias y las instituciones sociales; en segundo lugar, la pobreza y desigualdad económica; y por último, la participación y el compromiso de las instituciones públicas con la educación. Las conclusiones se centran en las prioridades de acción y los lineamientos de propuestas desde las percepciones evidenciadas para la construcción de cultura de paz en el territorio del caribe colombiano, que se centrarían principalmente en algunas perspectivas de mediación educativas y socioeducativas (entre lo escolar y lo comunitario).The purpose of the research presented in this paper is to analyze the community and scholar conflict phenomenon in the Caribbean coast of Colombia and the formative needs of vulnerable educational communities. The research was made with a Mixed-Method approach, using and applying different techniques, instruments and strategies from qualitative and quantitative methods like surveys to a 344 sample (teachers and educational community), 7 focus groups and 35 interviews to families and social agents. The results and discussion shows a descriptive analysis linked to the main needs and problematic situations of (a) the social community linked to vulnerability: unemployment, violence and lack of social coverture (basic services covered by the government: supplies, housing, etc.) and (b) the educational community: social mediation in schools with the families and social entities; poverty and economic inequality and participation and engagement of public entities with education. The conclusions are focused on the action priorities and guidelines to develop proposals (based on the perceptions observed) to build a culture of peace in the Caribbean Region of Colombia. These Guidelines would turn into educational and sociocultural mediations (between the communities and the school)

Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer¿s disease

The accumulation of neurofibrillary tangles in Alzheimer’s disease (AD) propagates with characteristic spatiotemporal patterns which follow brain network connections, implying trans-synaptic transmission of tauopathy. Since misfolded tau has been shown to transmit across synapses in AD animal models, we hypothesized that synapses in AD patients may contain misfolded tau. By immunofluorescence imaging of bipartite synapses from AD subjects, we detected tau protein in 38.4% of presynaptic and 50.9% of postsynaptic terminals. The pre/post distribution for hyperphosphorylated tau was 26.9%/30.7%, and for misfolded tau 18.3%/19.3%. In the temporal cortex, microscopic aggregates of tau, containing ultra-stable oligomers, were estimated to accumulate within trillions of synapses, outnumbering macroscopic tau aggregates such as tangles by 10000 fold. Non-demented elderly also showed considerable synaptic tau hyperphosphorylation and some misfolding, implicating the synapse as one of the first subcellular compartments affected by tauopathy. Misfolding of tau protein appeared to occur in situ inside synaptic terminals, without mislocalizing or mistrafficking. Misfolded tau at synapses may represent early signs of neuronal degeneration, mediators of synaptotoxicity, and anatomical substrates for transmitting tauopathy, but its actual role in these processes remain to be elucidated. Electronic supplementary material The online version of this article (doi:10.1186/s40478-014-0146-2) contains supplementary material, which is available to authorized users

Beneficial effect of human anti-amyloid-β active immunization on neurite morphology and tau pathology

Anti-amyloid-β immunization leads to amyloid clearance in patients with Alzheimer's disease, but the effect of vaccination on amyloid-β-induced neuronal pathology has not been quantitatively examined. The objectives of this study were to address the effects of anti-amyloid-β active immunization on neurite trajectories and the pathological hallmarks of Alzheimer's disease in the human hippocampus. Hippocampal sections from five patients with Alzheimer's disease enrolled in the AN1792 Phase 2a trial were compared with those from 13 non-immunized Braak-stage and age-matched patients with Alzheimer's disease, and eight age-matched non-demented controls. Analyses included neurite curvature ratio as a quantitative measure of neuritic abnormalities, amyloid and tau loads, and a quantitative characterization of plaque-associated neuritic dystrophy and astrocytosis. Amyloid load and density of dense-core plaques were decreased in the immunized group compared to non-immunized patients (P < 0.01 and P < 0.001, respectively). The curvature ratio in non-immunized patients with Alzheimer's disease was elevated compared to non-demented controls (P < 0.0001). In immunized patients, however, the curvature ratio was normalized when compared to non-immunized patients (P < 0.0001), and not different from non-demented controls. In the non-immunized patients, neurites close to dense-core plaques (within 50 µm) were more abnormal than those far from plaques (i.e. beyond 50 µm) (P < 0.0001). By contrast, in the immunized group neurites close to and far from the remaining dense-core plaques did not differ, and both were straighter compared to the non-immunized patients (P < 0.0001). Compared to non-immunized patients, dense-core plaques remaining after immunization had similar degree of astrocytosis (P = 0.6060), more embedded dystrophic neurites (P < 0.0001) and were more likely to have mitochondrial accumulation (P < 0.001). In addition, there was a significant decrease in the density of paired helical filament-1-positive neurons in the immunized group as compared to the non-immunized (P < 0.05), but not in the density of Alz50 or thioflavin-S positive tangles, suggesting a modest effect of anti-amyloid-β immunization on tangle pathology. Clearance of amyloid plaques upon immunization with AN1792 effectively improves a morphological measure of neurite abnormality in the hippocampus. This improvement is not just attributable to the decrease in plaque load, but also occurs within the halo of the remaining dense-core plaques. However, these remaining plaques still retain some of their toxic potential. Anti-amyloid-β immunization might also ameliorate the hippocampal tau pathology through a decrease in tau phosphorylation. These data agree with preclinical animal studies and further demonstrate that human anti-amyloid-β immunization does not merely clear amyloid from the Alzheimer's disease brain, but reduces some of the neuronal alterations that characterize Alzheimer's diseas

Thermal and mechanical effects of different excitation modes based on low frequency laser modulation in optical hyperthermia

The low frequency modulation of the laser source (menor que30KHz) allows the generation of a pulsed signal that intermittently excites the gold nanorods. The temperature curves obtained for different frequencies and duty cycles of modulation but with equal average power and identical laser parameters, show that the thermal behavior in continuous wave and modulation modes is the same. However, the cell death experiments suggest that the percentage of death is higher in the cases of modulation. This observation allows us to conclude that there are other effects in addition to temperature that contribute to the cellular death. The mechanical effects like sound or pressure waves are expected to be generated from thermal expansion of gold nanorods. In order to study the behavior and magnitude of these processes we have developed a measure device based on ultrasound piezoelectric receivers (25KHz) and a lock-in amplifier that is able to detect the sound waves generated in samples of gold nanorods during laser irradiation providing us a voltage result proportional to the pressure signal. The first results show that the pressure measurements are directly proportional to the concentration of gold nanorods and the laser power, therefore, our present work is focused on determine the real influence of these effects in the cell death process