Pharmacological experiment on neurodegeneration in mature trisomic mouse models: Assessment of the neurodegenerative phenotype and its potential modulation in a middle-aged mouse model of Down syndrome
Pharmacological experiment on neurodegeneration in mature trisomic mouse models: Assessment of the neurodegenerative phenotype and its potential modulation in a middle-aged mouse model of Down syndrome
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Resum
Down syndrome (DS) is the most common cause of intellectual disability and a genetic cause of early Alzheimer’s disease, produced by trisomy of whole or part of chromosome 21. Nevertheless, no gold-standard clinical treatment exists yet. The endocannabinoid system plays an important role in memory performance, being implicated in the pathophysiology of DS. Previously in the hosting laboratory, cannabinoid type-1 receptor (CB1R) function and expression were found enhanced in the hippocampus of young-adult trisomic (2-3 months old) Ts65Dn mice, the most used preclinical model of DS. A sub- chronic (7 days) pharmacological treatment with the CB1R antagonist rimonabant was observed to restore object-recognition memory in trisomic mice. Recently, the group found that long-term oral treatment with rimonabant also restored memory performance in middle-aged (10 months old) trisomic mice, an age when trisomic mice display a noticeable neurodegeneration, resembling Alzheimer’s disease observed in aged DS subjects. The purpose of the present study was to examine the neurodegenerative phenotype of trisomic mice after the long-term pharmacological inhibition of CB1R. A semi-automatic quantification method was developed to analyse cellular features from brain histological preparations. Analysis of locus coeruleus noradrenergic neurons showed a significant lost in trisomic mice that was not prevented by rimonabant treatment. Cholinergic neurodegeneration was not prevented by the treatment, and was only found in the medial septum, but not in other basal forebrain areas of trisomic mice. Together, despite the proven beneficial effects of rimonabant in memory performance, no effect of treatment was observed in the neurodegenerative phenotype of trisomic mice which clearly dissociates the pro-cognitive effect of rimonabant from the possibility of preventing neurodegeneration.Descripció
Tutors: Andrés Ozaita Mintegui, Anna Vázquez Oliver