RESUMEN
In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aß) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aß and mediates Aß-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aß. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aß deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aß deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing ß-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aß toxicity and would be a novel therapeutic target and biomarker for AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Encéfalo/patología , Proteínas del Tejido Nervioso/química , Estructura Terciaria de Proteína/fisiología , Receptores de Factor de Crecimiento Nervioso/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Factores de Edad , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Precursor de Proteína beta-Amiloide/genética , Animales , Apoptosis/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estudios de Casos y Controles , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/terapia , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Humanos , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Mutación/genética , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Presenilina-1/genética , Receptores de Factor de Crecimiento Nervioso/deficiencia , Receptores de Factor de Crecimiento Nervioso/genética , Proteínas Recombinantes/uso terapéutico , Transducción GenéticaRESUMEN
The aim of this study was to investigate the effect of short-term forced exercise protocol on passive avoidance retention in morphine-exposed rats. Effects of morphine on acquisition and retrieval of retention have been proven in the avoidance paradigms. Twenty four male Wistar rats weighing 250-300 g were used in this study. Animals were randomly divided into four groups including: (1) non-morphine-exposed without exercise (nA.nE) (2) non-morphine-exposed with exercise (nA.E) (3) morphine-exposed without exercise (A.nE) and (4) morphine-exposed with exercise (A.E). Rats ran as forced exercise on the motorized treadmill 1 h daily for ten days. Morphine-exposed animals received intraperitoneal morphine during first 5 days of the exercise period and their dependence to morphine was confirmed by naloxane admistration (10 mg kg(-1), i.p.) and withdrawal test. After 10 days of forced exercise, step down latency was tested and Inflexion Ratio (IR) was evaluated in each rat. Baseline step down latencies before any morphine exposing or exercise have shown no significant alteration in all groups. Inflexion Ratio (IR) ofnA.E group has increased significantly (p<0.001) at 1, 3, 7 and 14 days after receiving shock (learning) compared to nA.nE and A.E groups. Our data showed that short-term forced exercise on treadmill improved retention in both morphine-exposed and non morphine-exposed rats at least up to 7 days and more than 14 days, respectively. Alteration in retention between exercised groups may attribute the release of adrenal stress hormones such as epinephrine and corticosterone because of the emotional arousal.