RESUMEN
Accumulation of beta-amyloid (Aß) in the brain has been implicated as a major contributor to the cellular pathology and cognitive impairment observed in Alzheimer's disease. Beta-amyloid may exert its toxic effects by increasing reactive oxygen species and neuroinflammation in the brain. This study set out to investigate whether a genetically engineered derivative of the peroxisomal antioxidant enzyme catalase (CAT-SKL), is able to reduce the toxicity induced by intracerebroventricular injection of Aß25-35 in the mature rat brain. Histopathological and immunohistochemical analyses were used to evaluate neuroinflammation, and neuronal loss. Spatial learning and reference memory was assessed using the Morris water maze. CAT-SKL treatment was able to reduce the pathology induced by Aß25-35 toxicity by significantly decreasing microglia activation in the basal forebrain and thalamus, and reducing cholinergic loss in the basal forebrain. Aß25-35 animals showed deficits in long-term reference memory in the Morris water maze, while Aß25-35 animals treated with CAT-SKL did not demonstrate long-term memory impairments. This preclinical data provides support for the use of CAT-SKL in reducing neuroinflammation and long-term reference memory deficits induced by Aß25-35.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Antioxidantes/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Fragmentos de Péptidos/toxicidad , Animales , Encéfalo/enzimología , Catalasa/análisis , Muerte Celular , Evaluación Preclínica de Medicamentos , Discapacidades para el Aprendizaje/tratamiento farmacológico , Discapacidades para el Aprendizaje/prevención & control , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/prevención & control , Microglía/efectos de los fármacos , Microglía/fisiología , Proteínas del Tejido Nervioso/análisis , Neuronas/efectos de los fármacos , Neuronas/patología , Prosencéfalo/química , Prosencéfalo/efectos de los fármacos , Prosencéfalo/patología , Distribución Aleatoria , Ratas , Ratas Wistar , Aprendizaje Espacial/efectos de los fármacos , Tálamo/química , Tálamo/efectos de los fármacos , Tálamo/patologíaRESUMEN
Alzheimer's disease (AD) is a debilitating neurodegenerative disease that results in neurodegeneration and memory loss. While age is a major risk factor for AD, stroke has also been implicated as a risk factor and an exacerbating factor. The co-morbidity of stroke and AD results in worsened stroke-related motor control and AD-related cognitive deficits when compared to each condition alone. To model the combined condition of stroke and AD, a novel transgenic rat model of AD, with a mutated form of amyloid precursor protein (a key protein involved in the development of AD) incorporated into its DNA, is given a small unilateral striatal stroke. For a model with the combination of both stroke and AD, behavioral tests that assess stroke-related motor control, locomotion and AD-related cognitive function must be implemented. The cylinder task involves a cost-efficient, multipurpose apparatus that assesses spontaneous forelimb motor use. In this task, a rat is placed in a cylindrical apparatus, where the rat will spontaneously rear and contact the wall of the cylinder with its forelimbs. These contacts are considered forelimb motor use and quantified during video analysis after testing. Another cost-efficient motor task implemented is the beam-walk task, which assesses forelimb control, hindlimb control and locomotion. This task involves a rat walking across a wooden beam allowing for the assessment of limb motor control through analysis of forelimb slips, hindlimb slips and falls. Assessment of learning and memory is completed with Morris water maze for this behavioral paradigm. The protocol starts with spatial learning, whereby the rat locates a stationary hidden platform. After spatial learning, the platform is removed and both short-term and long-term spatial reference memory is assessed. All three of these tasks are sensitive to behavioral differences and completed within 28 days for this model, making this paradigm time-efficient and cost-efficient.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Modelos Animales de Enfermedad , Hipocampo/fisiología , Memoria a Corto Plazo/fisiología , Corteza Sensoriomotora/fisiología , Aprendizaje Espacial/fisiología , Accidente Cerebrovascular/fisiopatología , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/fisiopatología , Ratones , Ratas , Ratas TransgénicasRESUMEN
Total joint replacements can be subject to the loss of polyethylene material due to wear, leading to osteolysis and decreased implant longevity. Micro-computed tomography (micro-CT) techniques have recently been developed to calculate 3D surface deviations in worn implant components. We describe a micro-CT technique to measure the volume of the surface deviations (volume of wear plus creep) within a specific region or compartment, and report its repeatability and reproducibility. Six worn polyethylene tibial inserts were scanned using a laboratory micro-CT scanner and subsequently reconstructed at 50 µm voxel spacing. A previously developed custom software application was used to quantify the 3D surface deviations between the worn tibial inserts and an unworn reference geometry. Three observers (two trained and one expert) used new custom software to manually outline the localized regions of surface deviation (three times for each of the worn inserts) and calculate the volume of the deviations. The overall intraobserver variability in the surface deviation volumes was 3.6% medially and 1.1% laterally. The overall interobserver variability was 4.8% medially and 1.7% laterally. Placement of points in outlining the region of deviation contributed the greatest variability to the measurements. Repeatability and reproducibility of the volume measurements are similar to measurements of total (nonregional) wear volume including a previous micro-CT technique (10%), fluid displacement (4.8%), and radiographic measurements (15.7%). The principles of this technique can likely be used to measure regional wear and creep volume in knee and hip joint replacement components from wear simulator, pin-on-disk, and retrieval studies.