Estrés oxidativo, respuesta inmune, plasticidad sináptica y cognición en modelos transgénicos de la enfermedad de Alzheimer / Oxidative stress, the immune response, synaptic plasticity, and cognition in transgenic models of Alzheimer disease

Introducción: En el mundo, alrededor de 50 millones de personas padecen demencia; la forma más común es la enfermedad de Alzheimer (EA), que representa el 60-70% de los casos. Dada su alta incidencia, se hace imperativo diseñar estudios que permitan ampliar el conocimiento sobre su aparición y desarrollo, para proponer diagnósticos tempranos y/o posibles tratamientos. Una de las estrategias metodológicas que se han desarrollado son los modelos transgénicos murinos para el estudio de los factores involucrados en su etiología, y entre ellos, el estrés oxidativo y la respuesta inmune.DesarrolloSe realizó una búsqueda de artículos originales y revisiones en PubMed, Scopus y Google Scholar (2013-2019). En esta revisión abordamos dos factores que han sido estudiados de forma independiente: el estrés oxidativo y la respuesta inmune en modelos transgénicos para la EA, y se discute la relación que existe entre ellos y que impacta en la pérdida de la plasticidad sináptica y estructural, produciendo como efecto final el deterioro cognitivo.ConclusiónEsta revisión describe posibles mecanismos en donde participan el estrés oxidativo y la respuesta inmune sobre los efectos moleculares, celulares y conductuales en la EA, observando una estrecha relación entre estos elementos que conducen hacia el deterioro cognitivo. (AU)

Introduction: Worldwide, approximately 50 million people have dementia, with Alzheimer disease (AD) being the most common type, accounting for 60%-70% of cases. Given its high incidence, it is imperative to design studies to expand our knowledge about its onset and development, and to develop early diagnosis strategies and/or possible treatments. One methodological strategy is the use of transgenic mouse models for the study of the factors involved in AD aetiology, which include oxidative stress and the immune response.DevelopmentWe searched the PubMed, Scopus, and Google Scholar databases for original articles and reviews published between 2013 and 2019. In this review, we address two factors that have been studied independently, oxidative stress and the immune response, in transgenic models of AD, and discuss the relationship between these factors and their impact on the loss of synaptic and structural plasticity, resulting in cognitive impairment.ConclusionThis review describes possible mechanisms by which oxidative stress and the immune response participate in the molecular, cellular, and behavioural effects of AD, observing a close relationship between these factors, which lead to cognitive impairment. (AU)

Oxidative stress, the immune response, synaptic plasticity, and cognition in transgenic models of Alzheimer disease.

INTRODUCTION: Worldwide, approximately 50 million people have dementia, with Alzheimer disease (AD) being the most common type, accounting for 60%-70% of cases. Given its high incidence, it is imperative to design studies to expand our knowledge about its onset and development, and to develop early diagnosis strategies and/or possible treatments. One methodological strategy is the use of transgenic mouse models for the study of the factors involved in AD aetiology, which include oxidative stress and the immune response. DEVELOPMENT: We searched the PubMed, Scopus, and Google Scholar databases for original articles and reviews published between 2013 and 2019. In this review, we address 2 factors that have been studied independently, oxidative stress and the immune response, in transgenic models of AD, and discuss the relationship between these factors and their impact on the loss of synaptic and structural plasticity, resulting in cognitive impairment. CONCLUSION: This review describes possible mechanisms by which oxidative stress and the immune response participate in the molecular, cellular, and behavioural effects of AD, observing a close relationship between these factors, which lead to cognitive impairment.

Oxidative stress, the immune response, synaptic plasticity, and cognition in transgenic models of Alzheimer disease. / Estrés oxidativo, respuesta inmune, plasticidad sináptica y cognición en modelos transgénicos de la enfermedad de Alzheimer.

INTRODUCTION: Worldwide, approximately 50 million people have dementia, with Alzheimer disease (AD) being the most common type, accounting for 60%-70% of cases. Given its high incidence, it is imperative to design studies to expand our knowledge about its onset and development, and to develop early diagnosis strategies and/or possible treatments. One methodological strategy is the use of transgenic mouse models for the study of the factors involved in AD aetiology, which include oxidative stress and the immune response. DEVELOPMENT: We searched the PubMed, Scopus, and Google Scholar databases for original articles and reviews published between 2013 and 2019. In this review, we address two factors that have been studied independently, oxidative stress and the immune response, in transgenic models of AD, and discuss the relationship between these factors and their impact on the loss of synaptic and structural plasticity, resulting in cognitive impairment. CONCLUSION: This review describes possible mechanisms by which oxidative stress and the immune response participate in the molecular, cellular, and behavioural effects of AD, observing a close relationship between these factors, which lead to cognitive impairment.

Alteraciones en la corteza motora primaria en la enfermedad de Alzheimer: estudio en el modelo 3xTg-AD / Primary motor cortex alterations in Alzheimer disease: A study in the 3xTg-AD model

Introducción: En el cerebro del humano y en el de modelos animales, la enfermedad de Alzheimer (EA) se caracteriza por la acumulación del péptido β-amiloide (βA), de la proteína tau hiperfosforilada, degeneración neuronal y gliosis astrocítica que son prominentes en regiones cerebrales vulnerables (hipocampo y corteza). Estas alteraciones se relacionan con el deterioro cognitivo (pérdida de la memoria) y no cognitivo en la función motora. El objetivo de este trabajo fue identificar en el modelo (3xTg-AD) los cambios celulares (neuronas y astroglía) y la agregación de βA y tau hiperfosforilada en la corteza motora primaria (M1) en una etapa intermedia de la EA y su relación con el desempeño motor. Métodos: Se utilizaron hembras 3xTg-AD de 11 meses de edad, comparadas con no transgénicas (No-Tg) de la misma edad. En ambos grupos, se evaluaron el desempeño motor (campo abierto) y el daño celular con marcadores específicos: BAM10 (agregados βA extracelulares), tau 499 (hiperfosforilada), GFAP (astrocitos) y Klüver-Barrera (neuronas) en la M1. Resultados: Las hembras 3xTg-AD en etapa intermedia de la patología mostraron alteraciones motoras y celulares asociadas al depósito de βA y tau hiperfosforilada en la M1. Conclusiones: Desde etapas tempranas de la EA se observan signos y síntomas de deterioro funcional. Sin embargo, en este estudio reportamos que en la etapa intermedia de la patología se encuentran establecidas las características de daño en la M1 asociadas al desempeño motor. Eventos que se relacionan con el avance de las características clínicas de la patología

Introduction: In humans and animal models, Alzheimer disease (AD) is characterised by accumulation of amyloid-β peptide (Aβ) and hyperphosphorylated tau protein, neuronal degeneration, and astrocytic gliosis, especially in vulnerable brain regions (hippocampus and cortex). These alterations are associated with cognitive impairment (loss of memory) and non-cognitive impairment (motor impairment). The purpose of this study was to identify cell changes (neurons and glial cells) and aggregation of Aβ and hyperphosphorylated tau protein in the primary motor cortex (M1) in 3xTg-AD mouse models at an intermediate stage of AD. Methods: We used female 3xTg-AD mice aged 11 months and compared them to non-transgenic mice of the same age. In both groups, we assessed motor performance (open field test) and neuronal damage in M1 using specific markers: BAM10 (extracellular Aβ aggregates), tau 499 (hyperphosphorylated tau protein), GFAP (astrocytes), and Klüver-Barrera staining (neurons). Results: Female 3xTg-AD mice in intermediate stages of the disease displayed motor and cellular alterations associated with Aβ and hyperphosphorylated tau protein deposition in M1. Conclusions: Patients with AD display signs and symptoms of functional impairment from early stages. According to our results, M1 cell damage in intermediate-stage AD affects motor function, which is linked to progression of the disease

Primary motor cortex alterations in Alzheimer disease: A study in the 3xTg-AD model. / Alteraciones en la corteza motora primaria en la enfermedad de Alzheimer: estudio en el modelo 3xTg-AD.

INTRODUCTION: In humans and animal models, Alzheimer disease (AD) is characterised by accumulation of amyloid-ß peptide (Aß) and hyperphosphorylated tau protein, neuronal degeneration, and astrocytic gliosis, especially in vulnerable brain regions (hippocampus and cortex). These alterations are associated with cognitive impairment (loss of memory) and non-cognitive impairment (motor impairment). The purpose of this study was to identify cell changes (neurons and glial cells) and aggregation of Aß and hyperphosphorylated tau protein in the primary motor cortex (M1) in 3xTg-AD mouse models at an intermediate stage of AD. METHODS: We used female 3xTg-AD mice aged 11 months and compared them to non-transgenic mice of the same age. In both groups, we assessed motor performance (open field test) and neuronal damage in M1 using specific markers: BAM10 (extracellular Aß aggregates), tau 499 (hyperphosphorylated tau protein), GFAP (astrocytes), and Klüver-Barrera staining (neurons). RESULTS: Female 3xTg-AD mice in intermediate stages of the disease displayed motor and cellular alterations associated with Aß and hyperphosphorylated tau protein deposition in M1. CONCLUSIONS: Patients with AD display signs and symptoms of functional impairment from early stages. According to our results, M1 cell damage in intermediate-stage AD affects motor function, which is linked to progression of the disease.

Hippocampal mechanisms in impaired spatial learning and memory in male offspring of rats fed a low-protein isocaloric diet in pregnancy and/or lactation.

Maternal nutritional challenges during fetal and neonatal development result in developmental programming of multiple offspring organ systems including brain maturation and function. A maternal low-protein diet during pregnancy and lactation impairs associative learning and motivation. We evaluated effects of a maternal low-protein diet during gestation and/or lactation on male offspring spatial learning and hippocampal neural structure. Control mothers (C) ate 20% casein and restricted mothers (R) 10% casein, providing four groups: CC, RR, CR, and RC (first letter pregnancy, second lactation diet). We evaluated the behavior of young adult male offspring around postnatal day 110. Corticosterone and ACTH were measured. Males were tested for 2 days in the Morris water maze (MWM). Stratum lucidum mossy fiber (MF) area, total and spine type in basal dendrites of stratum oriens in the hippocampal CA3 field were measured. Corticosterone and ACTH were higher in RR vs. CC. In the MWM acquisition test CC offspring required two, RC three, and CR seven sessions to learn the maze. RR did not learn in eight trials. In a retention test 24 h later, RR, CR, and RC spent more time locating the platform and performed fewer target zone entries than CC. RR and RC offspring spent less time in the target zone than CC. MF area, total, and thin spines were lower in RR, CR, and RC than CC. Mushroom spines were lower in RR and RC than CC. Stubby spines were higher in RR, CR, and RC than CC. We conclude that maternal low-protein diet impairs spatial acquisition and memory retention in male offspring, and that alterations in hippocampal presynaptic (MF), postsynaptic (spines) elements and higher glucocorticoid levels are potential mechanisms to explain these learning and memory deficits.

Plasticidad sináptica estructural en el hipocampo inducida por la experiencia espacial y sus implicaciones en el procesamiento de información / Structural synaptic plasticity in the hippocampus induced by spatial experience and its implications in information processing

Introducción: Para formar memorias perdurables, es necesario que los grupos de neuronas encargados de procesar la información que adquirimos desarrollen la capacidad de reproducir los patrones de actividad que se forman a través de la experiencia. Desarrollo: Los cambios en la eficiencia sináptica permiten que las neuronas se organicen en «ensambles» y reproduzcan una y otra vez estos patrones de actividad. Entre los cambios en la eficiencia sináptica están las modificaciones en la estructura, las cuales tienden a perdurar por mucho tiempo y por ello se les vincula con la memoria a largo plazo. En la literatura existe amplia evidencia de que la experiencia promueve modificaciones en la estructura sináptica, particularmente en regiones como el hipocampo. Conclusión: Las implicaciones funcionales de estos cambios en el hipocampo incluyen un posible papel en la estabilización de los recuerdos adquiridos y en la codificación de nueva información

Introduction: Long-lasting memory formation requires that groups of neurons processing new information develop the ability to reproduce the patterns of neural activity acquired by experience. Development: Changes in synaptic efficiency let neurons organise to form ensembles that repeat certain activity patterns again and again. Among other changes in synaptic plasticity, structural modifications tend to be long-lasting which suggests that they underlie long-term memory. There is a large body of evidence supporting that experience promotes changes in the synaptic structure, particularly in the hippocampus. Conclusion: Structural changes to the hippocampus may be functionally implicated in stabilising acquired memories and encoding new information

Structural synaptic plasticity in the hippocampus induced by spatial experience and its implications in information processing. / Plasticidad sináptica estructural en el hipocampo inducida por la experiencia espacial y sus implicaciones en el procesamiento de información.

INTRODUCTION: Long-lasting memory formation requires that groups of neurons processing new information develop the ability to reproduce the patterns of neural activity acquired by experience. DEVELOPMENT: Changes in synaptic efficiency let neurons organise to form ensembles that repeat certain activity patterns again and again. Among other changes in synaptic plasticity, structural modifications tend to be long-lasting which suggests that they underlie long-term memory. There is a large body of evidence supporting that experience promotes changes in the synaptic structure, particularly in the hippocampus. CONCLUSION: Structural changes to the hippocampus may be functionally implicated in stabilising acquired memories and encoding new information.

Efecto de la tibolona en la densidad de las espinas dendríticas en el hipocampo de la rata / Effect of tibolone on dendritic spine density in the rat hippocampus

Introducción: El hipoestrogenismo produce estrés oxidativo (EO) y cambios en las neuronas del hipocampo (H) y reduce la densidad de las espinas dendríticas (ED). Estas alteraciones repercuten en la respuesta plástica del H. La terapia de sustitución intraperitoneal con estrógenos revierte estos efectos, pero no se sabe si ocurre lo mismo con la tibolona (TB). El objetivo fue comprobar los efectos neuroprotectivos de la TB administrada por vía oral a largo plazo y su capacidad para revertir la poda de ED de las neuronas piramidales (NP) del CA1 del H. Métodos: Ratas Sprague Dawley jóvenes: distribuidas en 3 grupos: control en proestro (Pro) y 2 grupos ovariectomizados (Ovx), uno suplementado con dosis diaria de TB (1 mg/kg), OvxTB, y otro con vehículo (OvxV), por 40 días. Se analizaron la peroxidación de lípidos y la densidad de las ED en 3 segmentos de la dendrita apical de las NP del CA1 del H. Resultados: La TB no redujo la peroxidación de lípidos en el H, pero recuperó la poda de espinas en las NP del CA1 del H, producida por la ovariectomía. Conclusiones: La terapia de sustitución estrogénica en el hipoestrogenismo por ovariectomía tiene un efecto protector

Introduction: Oestrogen deficiency produces oxidative stress (OS) and changes in hippocampal neurons and also reduces the density of dendritic spines (DS). These alterations affect the plastic response of the hippocampus. Oestrogen replacement therapy reverses these effects, but it remains to be seen whether the same changes are produced by tibolone (TB). The aim of this study was to test the neuroprotective effects of long-term oral TB treatment and its ability to reverse DS pruning in pyramidal neurons (PN) of hippocampal area CA1. Methods: Young Sprague Dawley rats were distributed in 3 groups: a control group in proestrus (Pro) and two ovariectomised groups (Ovx), of which one was provided with a daily TB dose (1 mg/kg), OvxTB and the other with vehicle (OvxV), for 40 days in both cases. We analysed lipid peroxidation and DS density in 3 segments of apical dendrites from PNs in hippocampal area CA1. Results: TB did not reduce lipid peroxidation but it did reverse the spine pruning in CA1 pyramidal neurons of the hippocampus which had been caused by ovariectomy. Conclusions: Oestrogen replacement therapy for ovariectomy-induced oestrogen deficiency has a protective effect on synaptic plasticity in the hippocampus

Efectos de la morfina en la plasticidad cerebral / Effects of morphine on brain plasticity

Introducción: La morfina, como otros opiáceos y las drogas de abuso, tiene la capacidad de modificar la plasticidad cerebral de las áreas que regulan la morfología neuronal de las dendritas y espinas, que son el sitio primario de sinapsis excitatorias en regiones cerebrales que regulan funciones de incentivo motivación, recompensa y aprendizaje. Objetivo: En la presente revisión se analizan aspectos del impacto del uso de la morfina durante los periodos prenatales del desarrollo cerebral y las consecuencias a largo plazo en murinos, para relacionar estos efectos que ocurren en el humano neonato y adulto. Desarrollo: La exposición repetida a la morfina en el tratamiento del dolor en enfermos terminales produce cambios a largo plazo en la densidad postsináptica de sitios (dendritas y espinas) en áreas sensibles del cerebro, como la corteza prefrontal y el sistema límbico (hipocampo, amígdala), así como en los núcleos caudado y accumbens. Este artículo revisa los mecanismos celulares implicados, principalmente de los receptores dopaminérgicos y glutamatérgicos, así como la plasticidad sináptica lograda por los cambios en las dendritas y espinas en esta área. Conclusiones: Las acciones de la morfina durante el desarrollo del cerebro y también en el cerebro adulto producen alteraciones en la plasticidad de sitios excitatorios postsinápticos, áreas del cerebro que están implicadas en las funciones del sistema límbico (la recompensa y el aprendizaje). Se necesitan más estudios sobre la plasticidad en las dendritas y espinas en sus moléculas de señalización, tales como el calcio, con el fin de mejorar el tratamiento de la adicción

Introduction: Morphine shares with other opiates and drugs of abuse the ability to modify the plasticity of brain areas that regulate the morphology of dendrites and spines, which are the primary sites of excitatory synapses in regions of the brain involved in incentive motivation, rewards, and learning. Objective: In this review we discuss the impact of morphine use during the prenatal period of brain development and its long-term consequences in murines, and then link those consequences to similar effects occurring in human neonates and adults. Development: Repeated exposure to morphine as treatment for pain in terminally ill patients produces long-term changes in the density of postsynaptic sites (dendrites and spines) in sensitive areas of the brain, such as the prefrontal cortex, the limbic system (hippocampus, amygdala), and caudate nuclei and nucleus accumbens. This article reviews the cellular mechanisms and receptors involved, primarily dopaminergic and glutamatergic receptors, as well as synaptic plasticity brought about by changes in dendritic spines in these areas. Conclusions: The actions of morphine on both developing and adult brains produce alterations in the plasticity of excitatory postsynaptic sites of the brain areas involved in limbic system functions (reward and learning). Doctors need further studies on plasticity in dendrites and spines and on signaling molecules, such as calcium, in order to improve treatments for addiction

Genetic markers in biological fluids for aging-related major neurocognitive disorder.

Aging-related major neurocognitive disorder (NCD), formerly named dementia, comprises of the different acquired diseases whose primary deficit is impairment in cognitive functions such as complex attention, executive function, learning and memory, language, perceptual/motor skills, and social cognition, and that are related to specific brain regions and/or networks. According to its etiology, the most common subtypes of major NCDs are due to Alzheimer' s disease (AD), vascular disease (VaD), Lewy body disease (LBD), and frontotemporal lobar degeneration (FTLD). These pathologies are frequently present in mixed forms, i.e., AD plus VaD or AD plus LBD, thus diagnosed as due to multiple etiologies. In this paper, the definitions, criteria, pathologies, subtypes and genetic markers for the most common age-related major NCD subtypes are summarized. The current diagnostic criteria consider cognitive decline leading to major NCD or dementia as a progressive degenerative process with an underlying neuropathology that begins before the manifestation of symptoms. Biomarkers associated with this asymptomatic phase are being developed as accurate risk factor and biomarker assessments are fundamental to provide timely treatment since no treatments to prevent or cure NCD yet exist. Biological fluid assessment represents a safer, cheaper and less invasive method compared to contrast imaging studies to predict NCD appearance. Genetic factors particularly have a key role not only in predicting development of the disease but also the age of onset as well as the presentation of comorbidities that may contribute to the disease pathology and trigger synergistic mechanisms which may, in turn, accelerate the neurodegenerative process and its resultant behavioral and functional disorders.

Effects of morphine on brain plasticity.

INTRODUCTION: Morphine shares with other opiates and drugs of abuse the ability to modify the plasticity of brain areas that regulate the morphology of dendrites and spines, which are the primary sites of excitatory synapses in regions of the brain involved in incentive motivation, rewards, and learning. OBJECTIVE: In this review we discuss the impact of morphine use during the prenatal period of brain development and its long-term consequences in murines, and then link those consequences to similar effects occurring in human neonates and adults. DEVELOPMENT: Repeated exposure to morphine as treatment for pain in terminally ill patients produces long-term changes in the density of postsynaptic sites (dendrites and spines) in sensitive areas of the brain, such as the prefrontal cortex, the limbic system (hippocampus, amygdala), and caudate nuclei and nucleus accumbens. This article reviews the cellular mechanisms and receptors involved, primarily dopaminergic and glutamatergic receptors, as well as synaptic plasticity brought about by changes in dendritic spines in these areas. CONCLUSIONS: The actions of morphine on both developing and adult brains produce alterations in the plasticity of excitatory postsynaptic sites of the brain areas involved in limbic system functions (reward and learning). Doctors need further studies on plasticity in dendrites and spines and on signaling molecules, such as calcium, in order to improve treatments for addiction.

Effect of tibolone on dendritic spine density in the rat hippocampus.

INTRODUCTION: Oestrogen deficiency produces oxidative stress (OS) and changes in hippocampal neurons and also reduces the density of dendritic spines (DS). These alterations affect the plastic response of the hippocampus. Oestrogen replacement therapy reverses these effects, but it remains to be seen whether the same changes are produced by tibolone (TB). The aim of this study was to test the neuroprotective effects of long-term oral TB treatment and its ability to reverse DS pruning in pyramidal neurons (PN) of hippocampal area CA1. METHODS: Young Sprague Dawley rats were distributed in 3 groups: a control group in proestrus (Pro) and two ovariectomised groups (Ovx), of which one was provided with a daily TB dose (1mg/kg), OvxTB and the other with vehicle (OvxV), for 40 days in both cases. We analysed lipid peroxidation and DS density in 3 segments of apical dendrites from PNs in hippocampal area CA1. RESULTS: TB did not reduce lipid peroxidation but it did reverse the spine pruning in CA1 pyramidal neurons of the hippocampus which had been caused by ovariectomy. CONCLUSIONS: Oestrogen replacement therapy for ovariectomy-induced oestrogen deficiency has a protective effect on synaptic plasticity in the hippocampus.

Marcaje colinérgico en la corteza cerebral y el hipocampo en algunas especies animales y su relación con la enfermedad de Alzheimer / Cholinergic markers in the cortex and hippocampus of some animal species and their correlation to Alzheimer’s disease

Introducción: El sistema colinérgico incluye neuronas localizadas en el cerebro basal anterior y sus axones largos proyectan a la corteza cerebral e hipocampo. Este sistema modula la función cognitiva. En la enfermedad de Alzheimer (EA) y en el proceso de envejecimiento la disfunción colinérgica hay una asociación entre el deterioro cognitivo y el daño progresivo de las fibras colinérgicas, lo que conduce al postulado de la hipótesis colinérgica. Desarrollo: En la EA se producen alteraciones en la expresión y en la actividad de la colina acetiltransferasa (ChAT) y la acetilcolinesterasa (AChE), enzimas específicas relacionadas con la función del SC. Ambas proteínas juegan un papel importante en la transmisión colinérgica mostrando variaciones en la corteza cerebral y en el hipocampo, tanto por el envejecimiento, como por la EA. En ambas estructuras, los desórdenes demenciales están asociados a la destrucción severa y desorganización de las proyecciones colinérgicas que se encuentran afectadas. Para el estudio de este sistema se han usado marcadores específicos como los anticuerpos contra ChAT y AChE que han sido empleados en las técnicas de inmuhistoquímica de luz y microscopia electrónica en algunas especies animales. Conclusiones: En este trabajo se hace una revisión de los principales estudios inmunomorfológicos de la corteza cerebral e hipocampo de varias especies animales con énfasis en el SC y su relación con la EA

Introduction: The cholinergic system includes neurons located in the basal forebrain and their long axons that reach the cerebral cortex and the hippocampus. This system modulates cognitive function. In Alzheimer’s disease (AD) and ageing, cognitive impairment is associated with progressive damage to cholinergic fibres, which leads us to the cholinergic hypothesis for AD. Development: The AD produces alterations in the expression and activity of acetyltransferase (ChAT) and acetyl cholinesterase (AChE), enzymes specifically related to cholinergic system function. Both proteins play a role in cholinergic transmission, which is altered in both the cerebral cortex and the hippocampus due to ageing and AD. Dementia disorders are associated with the severe destruction and disorganisation of the cholinergic projections extending to both structures. Specific markers, such as anti-ChAT and anti-AChE antibodies, have been used in light immunohistochemistry and electron microscopy assays to study this system in adult members of certain animal species. Conclusions: This paper reviews the main immunomorphological studies of the cerebral cortex and hippocampus in some animal species with particular emphasis on the cholinergic system and its relationship with the AD

REST/NRSF-induced changes of ChAT protein expression in the neocortex and hippocampus of the 3xTg-AD mouse model for Alzheimer's disease.

AIMS: The cholinergic system is one of the neurotransmitter systems altered in Alzheimer's disease (AD), the most common form of human dementia. The objective of this work was to determine the REST/NRSF involvement in altered ChAT expression in the neocortex and hippocampus of an AD transgenic mouse (homozygous 3xTg-AD) that over-expresses 3 proteins, amyloid-ß precursor protein, presenilin-1, and tau, all of which are associated with AD and cause cellular degeneration. MAIN METHODS: Two groups (WT and 3xTg-AD) of 11-month-old female mice were analyzed and compared. Half of the brains of each group were used for ChAT immunohistochemistry, and Western Blot analyses of ChAT and REST/NRSF were performed on the other half. KEY FINDINGS: We observed significant decreases in the number of ChAT-immunoreactive cells in the Meynert nucleus and of fibers in the frontal motor cortex and hippocampal CA1 area in transgenic mice compared with control mice. An increased level of REST/NRSF protein and a reduction of ChAT protein expression in the 3xTg-AD mice compared with their controls were also found in both in the latter two cerebral regions. SIGNIFICANCE: The increased REST/NRSF expression reported here and its effect on the regulatory region for ChAT transcription could explain the decreased expression of ChAT in the 3xTg-AD mouse; these findings may be associated with the degeneration observed in AD.

Deficits in odor-guided behaviors in the transgenic 3xTg-AD female mouse model of Alzheimer׳s disease.

Alzheimer׳s disease (AD) is characterized by a number of alterations including those in cognition and olfaction. An early symptom of AD is decreased olfactory ability, which may affect odor-guided behaviors. To test this possibility we evaluated alterations in sexual incentive motivation, sexual olfactory preference, sexual olfactory discrimination, nursing-relevant olfactory preference and olfactory discrimination in female mice. We tested 3xTg-AD (a triple transgenic model, which is a "knock in" of PS1M146V, APPSwe, and tauP300L) and wild type (WT) female mice when receptive (estrous) and non-receptive (anestrous). Subjects were divided into three groups of different ages: (1) 4-5 months, (2) 10-11 months, and (3) 16-18 months. In the sexual incentive motivation task, the receptive 3xTg-AD females showed no preference for a sexually active male at any age studied, in contrast to the WT females. In the sexual olfactory preference test, the receptive WT females were able to identify sexually active male secretions at all ages, but the oldest (16-18 months old) 3xTg-AD females could not. In addition, the oldest 3xTg-AD females showed no preference for nursing-relevant odors in dam secretions and were unable to discriminate between cinnamon and strawberry odors, indicating olfactory alterations. Thus, the present study suggests that the olfactory deficits in this mouse model are associated with changes in sexual incentive motivation and discrimination of food-related odors.

Cholinergic markers in the cortex and hippocampus of some animal species and their correlation to Alzheimer's disease.

INTRODUCTION: The cholinergic system includes neurons located in the basal forebrain and their long axons that reach the cerebral cortex and the hippocampus. This system modulates cognitive function. In Alzheimer's disease (AD) and ageing, cognitive impairment is associated with progressive damage to cholinergic fibres, which leads us to the cholinergic hypothesis for AD. DEVELOPMENT: The AD produces alterations in the expression and activity of acetyltransferase (ChAT) and acetyl cholinesterase (AChE), enzymes specifically related to cholinergic system function. Both proteins play a role in cholinergic transmission, which is altered in both the cerebral cortex and the hippocampus due to ageing and AD. Dementia disorders are associated with the severe destruction and disorganisation of the cholinergic projections extending to both structures. Specific markers, such as anti-ChAT and anti-AChE antibodies, have been used in light immunohistochemistry and electron microscopy assays to study this system in adult members of certain animal species. CONCLUSIONS: This paper reviews the main immunomorphological studies of the cerebral cortex and hippocampus in some animal species with particular emphasis on the cholinergic system and its relationship with the AD.

[Morphological analysis of the hippocampal region associated with an innate behaviour task in the transgenic mouse model (3xTg-AD) for Alzheimer disease]. / Análisis morfológico de la región del hipocampo asociado a una tarea conductual innata en el modelo de ratón transgénico (3xTg-AD) para la enfermedad de Alzheimer.

INTRODUCTION: Different animal models for Alzheimer disease (AD) have been designed to support the hypothesis that the neurodegeneration (loss of neurons and synapses with reactive gliosis) associated with Aß and tau deposition in these models is similar to that in the human brain. These alterations produce functional changes beginning with decreased ability to carry out daily and social life activities, memory loss, and neuropsychiatric disorders in general. Neuronal alteration plays an important role in early stages of the disease, especially in the CA1 area of hippocampus in both human and animal models. METHODS: Two groups (WT and 3xTg-AD) of 11-month-old female mice were used in a behavioural analysis (nest building) and a morphometric analysis of the CA1 region of the dorsal hippocampus. RESULTS: The 3xTg-AD mice showed a 50% reduction in nest quality associated with a significant increase in damaged neurons in the CA1 hippocampal area (26%±6%, P<.05) compared to the WT group. CONCLUSIONS: The decreased ability to carry out activities of daily living (humans) or nest building (3xTg-AD mice) is related to the neuronal alterations observed in AD. These alterations are controlled by the hippocampus. Post-mortem analyses of the human hippocampus, and the CA1 region in 3xTg-AD mice, show that these areas are associated with alterations in the deposition of Aß and tau proteins, which start accumulating in the early stages of AD.

Effect of 17ß-estradiol on zinc content of hippocampal mossy fibers in ovariectomized adult rats.

Sex hormones such as estrogen (17ß-estradiol) may modulate the zinc content of the hippocampus during the female estrous cycle. The mossy fiber system is highly plastic in the adult brain and is influenced by multiple factors including learning, memory, and stress. However, whether 17ß-estradiol is able to modulate the morphological plasticity of the mossy fibers throughout the estrous cycle remains unknown. Ovariectomized (Ovx) female 70- to 90-day-old Sprague-Dawley rats without or with estrogen supplement (OvxE) were compared with control rats in three stages of the estrous cycle: diestrus, proestrus, and estrus. The brain tissue from each of the five groups was processed with Timm's silver sulfide technique using the Image J program to measure the mossy fiber area in the stratum lucidum of CA3. Total zinc in the hippocampus was measured using Graphite Furnace Atomic Absorption Spectrophotometry. Two additional (Ovx and OvxE) groups were examined in spatial learning and memory tasks using the Morris water maze. Similar increases in total zinc content and mossy fiber area were observed. The mossy fiber area decreased by 26 ± 2 % (difference ± SEM percentages) in Ovx and 23 ± 4 % in estrus as compared to the proestrus group and by 18 ± 2 % in Ovx compared to OvxE. Additionally, only the OvxE group learned and remembered the task. These results suggest that estradiol has a significant effect on zinc content in hippocampal CA3 during the proestrus stage of the estrous cycle and is associated with correct performance in learning and memory.

Increase of mushroom spine density in CA1 apical dendrites produced by water maze training is prevented by ovariectomy.

Dendritic spine density increases after spatial learning in hippocampal CA1 pyramidal neurons. Gonadal activity also regulates spine density, and abnormally low levels of circulating estrogens are associated with deficits in hippocampus-dependent tasks. To determine if gonadal activity influences behaviorally induced structural changes in CA1, we performed a morphometric analysis on rapid Golgi-stained tissue from ovariectomized (Ovx) and sham-operated (Sham) female rats 7 days after they were given a single water maze (WM) training session (hidden platform procedure) or a swimming session in the tank containing no platform (SC). We evaluated the density of different dendritic spine types (stubby, thin, and mushroom) in three segments (distal, medial, and proximal) of the principal apical dendrite from hippocampal CA1 pyramidal neurons. Performance in the WM task was impaired in Ovx animals compared to Sham controls. Total spine density increased after WM in Sham animals in the proximal and distal CA1 apical dendrite segments but not in the medial. Interestingly, mushroom spine density consistently increased in all CA1 segments after WM. As compared to the Sham group, SC-Ovx rats showed spine pruning in all the segments, but mushroom spine density did not change significantly. In Ovx rats, WM training increased the density of stubby and thin, but not mushroom spines. Thus, ovariectomy alone produces spine pruning, while spatial learning increases spine density in spite of ovariectomy. Finally, the results suggest that mushroom spine production in CA1 after spatial learning requires gonadal activity, whereas this activity is not required for mushroom spine maintenance.