Alzheimer\u27s Disease: From Animal Models to the Human Syndrome

Some animal models, genetically modified (such as murine) and sporadic (as others species), enable the study of the origin of specific lesions observed in human neurodegenerative diseases. In particular, Alzheimer\u27s disease (AD) models have been designed to test the hypothesis that certain lesions are associated with functional and morphological changes beginning with memory loss and impairment in activities of daily life. This review compares and evaluates the phenotypes of different AD animal models, on the basis of the specific objectives of each study, with the purpose of encompassing their contributions to the comprehension of the AD signs and symptoms in humans. All these models contribute to the comprehension of the human AD mechanisms regarding the heterogeneity of AD phenotypes: the overlap between AD and age‐related changes, the variability of AD onset (early or late), the probable reactiveness of amyloid‐β and tau proteins, the scarcity of senile plaques and/or neurofibrillary tangles in some AD cases, the spatial correlation of the pathology and cerebral blood vessels, and the immunological responses (microglial aging) and synaptopathy. Altogether, these considerations may contribute to find therapies to treat and prevent this disease

Extinction procedure induces pruning of dendritic spines in CA1 hippocampal field depending on strength of training in rats

Numerous reports indicate that learning and memory of conditioned responses are accompanied by genesis of dendritic spines in the hippocampus, although there is a conspicuous lack of information regarding spine modifications after behavioral extinction. There is ample evidence that treatments that typically produce amnesia become innocuous when animals are submitted to a procedure of enhanced training. We now report that extinction of inhibitory avoidance (IA), trained with relatively low foot-shock intensities, induces pruning of dendritic spines along the length of the apical dendrites of hippocampal CA1 neurons. When animals are trained with a relatively high foot-shock there is a high resistance to extinction, and pruning in the proximal and medial segments of the apical dendrite are seen, while spine count in the distal dendrite remains normal. These results indicate that pruning is involved in behavioral extinction, while maintenance of spines is a probable mechanism that mediates the protecting effect against amnesic treatments produced by enhanced training

Morris water maze overtraining increases the density of thorny excrescences in the basal dendrites of CA3 pyramidal neurons

The hippocampus plays a fundamental role in spatial learning and memory. Dentate gyrus (DG) granular neurons project mainly to proximal apical dendrites of neurons in the CA3 stratum lucidum and also, to some extent, to the basal dendrites of CA3 pyramidal cells in the stratum oriens. The terminal specializations of DG neurons are the mossy fibers (MF), and these huge axon terminals show expansion in the CA3 stratum oriens after the animals undergo overtraining in the Morris Water Maze task (MWM). However, to our knowledge there are no reports regarding the possible changes in density of post-synaptic targets of these terminals in the basal dendrites of CA3 neurons after overtraining in the MWM. The purpose of this work was to study the density of thorny excrescences (TE) and other dendritic spine types (stubby, thin, and mushroom) in the CA3 stratum oriens in animals overtrained in the MWM for three consecutive days and in animals trained for only one day. Seven days after MWM training, the animals were sacrificed, and their brains removed and processed for rapid Golgi staining to visualize the different types of dendritic protrusions. Our results revealed that the relative quantity of stubby, thin, and mushroom dendritic spines did not change, regardless of amount of training. However, a significant increase in the density of TE was detected in the overtrained animals. These results strongly suggest that spatial water maze overtraining induces an increased density of MF–TE connections, which might be functionally relevant for long-term spatial memory formation.Fil: Gómez Padilla, Eurídice. Universidad Autonoma de Queretaro.; MéxicoFil: Bello Medina, Paola C.. Universidad Nacional Autónoma de México; MéxicoFil: León Jacinto, Uriel. Universidad Nacional Autónoma de México; MéxicoFil: Orta Salazar, Erika. Universidad Nacional Autónoma de México; MéxicoFil: Quirarte, Gina L.. Universidad Nacional Autónoma de México; MéxicoFil: Ramirez Amaya, Victor. 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; Argentina. Universidad Autonoma de Queretaro.; MéxicoFil: Prado Alcalá, Roberto A.. Universidad Nacional Autónoma de México; MéxicoFil: Díaz Cintra, Sofía. Universidad Nacional Autónoma de México; Méxic

Neurobiological bases of neuronal aging

Tema del mesArtículo el cual inicia con el significado de la compasión para después abordarla desde la perspectiva de género, además de hacer una observación del cerebro compasivo a través de una resonancia magnética; por otro lado se proponen algunas respuestas relacionadas al por qué sentimos diferente la compasión. El envejecimiento provoca cambios irreversibles que afectan células, tejidos y órganos. Conforme avanza la edad, ocurren alteraciones en las funciones mentales, coordinación motora y en patrones del sueño; disminuyen el peso y volumen cerebral, debido a la reducción de neuronas, vasos sanguíneos. También disminuyen las principales hormonas, estrógenos y progesterona en la menopausia, la testosterona y andrógenos en la andropausia, el eje hormonal del crecimiento y el factor de crecimiento insulínico en la somatopausia. Existen diversas teorías del por qué ocurre el envejecimiento: una es genética, debido al mecanismo de replicación del DNA; otra se refiere al estrés oxidativo, con una disfunción mitocondrial y la teoría de los radicales libres que postula un daño sostenido por la exposición de oxidantes, desencadenando una serie de procesos dañinos que se asocian al desarrollo de numerosas enfermedades. Durante el proceso de envejecimiento en la mujer, se advierte la pérdida de los esteroides sexuales lo que explica el deterioro cognitivo y la neurodegeneración aumentando la incidencia de enfermedades como Alzheimer y Parkinson. En el cerebro, los estrógenos participan en la integridad neuronal y en su plasticidad. Pero ¿Como enfrentarse al envejecimiento cerebral? La principal estrategia es el tratamiento correcto de los factores de riesgo. Cada día toma más relevancia una adecuada ingesta de antioxidantes en la dieta. Actualmente y dado que el promedio de vida se ha alargado, las investigaciones a nivel neuronal de este proceso han recibido especial atención y de manera importante en aquellas estructuras cerebrales que regulan funciones como la memoria. Estas áreas son susceptibles a cambios medioambientales que desencadenan procesos de plasticidad neuronal para adaptarse o bien ser el sitio en el que se inician los cambios progresivos e irreversibles neuronales. El conocimiento profundo de estos cambios a lo largo de la vida hace factible su previsión. Los estudios anti-edad se relacionan desde los hábitos de vida de los individuos, hasta los factores de riesgo que propician entre otros, el estrés oxidativo que hoy en día es la principal fuente del envejecimiento neuronalCompassion is a moral emotion elicited by the perception of other’s suffering and motivate helping behaviors. The neurobiological research on moral emotions employs the scanning of the brain activity with neuroimaging techniques while subjects perceive emotional and moral stimuli. This article describes the work performed to form a collection of pictures eliciting compassion and the identification of the brain activity related to view these pictures. One group of these pictures were classified as highly compassionate and were used in a event-related design to acquire the brain activity related to their watching by using functional magnetic resonance imaging. Behavioral results indicate that the experience of compassion is elicited by viewing expression of physical pain or illness, and it is associated with experiences of negative emotions, such as, displeasure, excitation and dominance, and both women and men experienced compassion similarly. Functional brain data showed that women accomplish the experience of compassion through a more complex neural activity related with emotions, memory and executive functions. Men process compassion through bran orbitofrontal brain activity related with moral learning. Gender differences are attributable to both, biological processes selected during our primate natural history and cultural patterns learned into family and parental dynamics.The aging causes irreversible changes affecting cells, tissues and organs, as the age, occur alterations in the mental functions, motor coordination and sleep patterns; reducing the weight and volume cerebral, due to the reduction of neurons and blood vessels. Also decrease the main hormones, estrogen and progesterone in menopause, testosterone and androgens in the andropause, the axis hormonal growth and growth factor insulin in the somatopause. There are several theories of why occurs on aging, one is genetic, due to the mechanism of replication of DNA, another refers to the oxidative stress, with a mitochondrial dysfunction and the theory of the free radicals that posits a damage sustained by the exposure of oxidizers, triggering a series of processes harmful to be associated with the development of many diseases. During the process of aging in women, warns the loss of the sex steroid which explains the cognitive impairment and the neurodegeneration increasing incidence of diseases such as Alzheimer’s and Parkinson. In the CNS, estrogen is participating in the neuronal integrity and its plasticity. But how confronting brain aging? The main strategy is the correct treatment of the risk factors; each day takes more relevance adequate intake of antioxidants in the diet. Today, and given that the average life has been lengthened, the investigations at the neural level of this process has received special attention and so important in those brain structures that regulate functions as the memory. These areas are susceptible to environmental changes triggering processes of plasticity neuronal to adapt or be the site where they start the progressive changes and irreversible neuron. The deep knowledge of these changes over the life makes it possible its forecast, the studies anti-aging relate from life habits of individuals, until the risk factors that encourage among others, the oxidative stress today the main source of aging neurona

Olfatory behaviour in a murine alzheimer model

Tema del mesEn el Instituto de Neurobiología campus UNAM-Juriquilla se estudian los aspectos conductuales, neuronales y moleculares, relacionados con la enfermedad de Alzheimer (EA) en un modelo de ratón transgénico (3XTg-AD, donado por el Dr. F. LaFerla, de la Universidad de California) y que es homocigótico para las tres proteínas humanas asociadas a la enfermedad. La ventaja de trabajar con este modelo es que además de su viabilidad, permite estudiar los cambios progresivos de las alteraciones neuronales, principalmente en las áreas más susceptibles como son la corteza cerebral y el hipocampo. En el humano, un aspecto del diagnóstico temprano de la enfermedad se relaciona con la disminución en la calidad de la olfacción que culmina con la incapacidad para discriminar diferentes olores volátiles, un aspecto relacionado con la presencia de agregados de beta amiloide en el bulbo olfatorio principal (BOP). Nuestro interés se centra en caracterizar la discriminación olfativa en el ratón transgénico (3xTg-AD) que es un homocigoto para la ED, con la finalidad de comprobar si también se presenta una alteración temprana asociada a la patología. Hasta ahora los datos obtenidos, a través de las pruebas conductuales de preferencia y motivación olfatoria, demuestran un deterioro en la olfacción del 3xTg-AD a los 10 meses de edad, principalmente asociada al BOPAt the Institute of Neurobiology UNAM campus-Juriquilla explores behavioral, neural and molecular aspects, associated with Alzheimer’s Disease (EA) in a model of transgenic mouse (3XTg-AD), donated by Dr. F. LaFerla, at the University of California, and that is homozygous for the three human proteins associated with the disease. The advantage of working with this model is that in addition to its viability, allows us to study the progressive changes of the neuronal alterations mainly in the areas more susceptible as are the cerebral cortex and the hippocampus. In the human, an aspect of early diagnosis of the disease is related to the decline in the quality of the olfaction that culminates with the inability to discriminate different smells volatile an issue relating to the presence of aggregates of beta amyloid in the olfactory bulb main (BOP). Our interest focuses on characterize the olfactory discrimination in the transgenic mouse (3xTg-AD) that is a homozygous for ED, with the aim of check if also an alteration early associated with the pathology. Until now the data obtained through the evidence behavioral preference and the olfactory motivation showed deterioration in the smelling of 3xTg-AD for the 10 months of age, mainly associated with the BO

Hippocampal Synaptic Expansion Induced by Spatial Experience in Rats Correlates with Improved Information Processing in the Hippocampus

<div><p>Spatial water maze (WM) overtraining induces hippocampal mossy fiber (MF) expansion, and it has been suggested that spatial pattern separation depends on the MF pathway. We hypothesized that WM experience inducing MF expansion in rats would improve spatial pattern separation in the hippocampal network. We first tested this by using the the delayed non-matching to place task (DNMP), in animals that had been previously trained on the water maze (WM) and found that these animals, as well as animals treated as swim controls (SC), performed better than home cage control animals the DNMP task. The “catFISH” imaging method provided neurophysiological evidence that hippocampal pattern separation improved in animals treated as SC, and this improvement was even clearer in animals that experienced the WM training. Moreover, these behavioral treatments also enhance network reliability and improve partial pattern separation in CA1 and pattern completion in CA3. By measuring the area occupied by synaptophysin staining in both the <i>stratum oriens</i> and the <i>stratun lucidum</i> of the distal CA3, we found evidence of structural synaptic plasticity that likely includes MF expansion. Finally, the measures of hippocampal network coding obtained with catFISH correlate significantly with the increased density of synaptophysin staining, strongly suggesting that structural synaptic plasticity in the hippocampus induced by the WM and SC experience is related to the improvement of spatial information processing in the hippocampus.</p></div

Synaptophysin/Map2 Split Channel and Higher Magnification Images.

<p>Immonostained tissue for synaptophysin and Map2 imaged with the Zeiss ApoTome™ system, equipped with a motorized stage which allows the acquisition of montage or mosaic images with the MosaiX software. Images were taken with the 25X/0.8 NA objective. One Zeiss LSM file containing the MosaiX montage was open using imageJ software and the color channels were separated (split channels). Then each channel went through the median filter and assigned its representative color. The nuclear counterstaining DAPI is shown in blue (A for CA1 and E for CA3). Map 2 is shown in Green (B for CA1 and F for CA3) and synaptophysin is shown in RED (C for CA1 and G for CA3). The merge colors image is shown in D for CA1 and H for CA3. The magnification shown here was done by only trimming the montage image and by applying a regular zoom-in using adobe photoshop. This is a proper example of the image resolution the experimenter had available for analysis (He can perform the same simple zoom-in magnification with the same results), and was obtained from a similar montage image as those shown in Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132676#pone.0132676.g006" target="_blank">6</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132676#pone.0132676.g008" target="_blank">8</a>. Calibration bar (lower right) represents 200 μm.</p

Synaptophysin/Map2 segmentation and Map2 staining area analysis.

<p>(A) A representative synaptophysin (Red) / Map2 (Green) stained image is shown with the drawings that defined the different hippocampal dendritic segments regions of interest (hippocampal segments ROIs). These hippocampal segments ROIs included the CA3 <i>stratum oriens</i>, divided into 3 regions based on their proximity to the dentate gyrus (DG): <i>stratum oriens distal</i> (<i>SOd</i>), <i>stratum oriens medial</i> (<i>SOm</i>), and <i>stratum oriens proximal</i> (<i>SOp</i>); the CA3 <i>stratum lucidum</i> was also divided into 3 regions, the <i>stratum lucidum distal</i> (<i>SLd</i>), <i>stratum lucidum medial</i> (<i>SLm</i>), and <i>stratum lucidum proximal</i> (<i>SLp</i>). The CA3 <i>stratum radiatum</i> was divided into 6 regions, depending on their proximity to the DG and to the pyramidal cell soma: <i>stratum radiatum distal medial</i> (<i>SRdm</i>), <i>stratum radiatum medial medial</i> (<i>SRmm</i>), <i>stratum radiatum proximal medial</i> (<i>SRpm</i>), <i>stratum radiatum distal distal</i> (<i>SRdd</i>), <i>stratum radiatum medial distal</i> (<i>SRmd</i>), and <i>stratum radiatum proximal distal</i> (<i>SRpd</i>). Finally, the last 2 ROIs correspond to the CA1 <i>stratum oriens</i> (CA1 <i>SO</i>) and the CA1 <i>stratum radiatum</i> (CA1 <i>SR</i>). In the bar graph (B) the Map2-stained area expressed in pixels is shown for each hippocampal segment ROI. It is important to emphasise that No significant differences were found among groups (IC, SC, and WM) in the Map2-stained area used for the synaptophysin analysis.</p