Ruparelia, AH; (2013) Axonal transport in mouse models of Down syndrome. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Down syndrome (DS) is a complex condition resulting in the most common genetic form of intellectual disability. Trisomy of chromosome 21 in humans (Hsa21) causes DS, likely due to overexpression of some of the 500 genes on this chromosome. People with DS are more susceptible to early-onset Alzheimer Disease (AD), and the histopathological and endocytic perturbations that characterise AD are present at an earlier age in people with DS than the general population with AD. They also display aberrant dendritic spine morphology, which is associated with learning and memory deficits. The Ts65Dn mouse model of DS carries 122 genes on its translocated chromosome and recapitulates these DS-associated phenotypes. Neurodegeneration in these mice may be caused by impaired retrograde axonal transport of essential neurotrophic factors. The triplication of the Hsa21-encoded amyloid precursor protein (APP) gene is proposed to cause enlarged early endosomes and a perturbed endocytic pathway that subsequently leads to axonal transport deficits. However the genetic contribution of other Hsa21 genes to axonal transport deficits remains unknown. The research in this thesis aimed to recapitulate the axonal transport, endocytic and dendritic phenotypes in Ts65Dn mice, and to elucidate the contribution of Hsa21 genes, to the pathogenesis of these deleterious phenotypes. Live-cell imaging of quantum dot-labelled brain-derived neurotrophic factor (BDNF) in Ts65Dn hippocampal neurons revealed impaired BDNF axonal transport. Neurons from these mice also displayed a greater number of enlarged early endosomes and reduced dendritic surface area and volume. The Ts1Rhr mouse model encodes 31 duplicated genes that are orthologous to the human DS critical region (DSCR), and has disomic APP expression levels. Ts1Rhr hippocampal neurons also revealed impaired BDNF axonal transport, however endosomal and dendritic morphology was spared. This suggests that in addition to APP, one or more genes orthologous to the human DSCR may be necessary for axonal transport deficits but not for the enlarged early endosome phenotype or dendritic abnormalities. Other putative mechanisms, such as perturbed cytoskeleton and motor protein function, may additionally exacerbate impaired axonal transport of neurotrophins.

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