Choong, XY;
(2015)
Investigating contributions of trisomy 21 in Down syndrome to Alzheimer disease phenotypes in a novel mouse cross.
Doctoral thesis , UCL (University College London).
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Abstract
Down syndrome (DS) is a common, complex disorder caused by having an extra copy of human chromosome 21 (trisomy 21). While clinical presentation varies extensively, Alzheimer disease (AD) pathology is found in brains of virtually all people with DS by 40 years. This increases their dementia risk such that one third of the DS population develops AD by 60 years. Therefore DS allows the investigation of pathogenetic mechanisms underlying its clear genetic form of early-onset AD. To model DS in mice, a ‘transchromosomic’ model, Tc1, was generated carrying a freely segregating copy of human chromosome 21 (Hsa21), which is trisomic for ~75% of Hsa21 genes. However, Tc1 is not functionally trisomic for APP. By crossing Tc1 with the J20 model, a transgenic mouse overexpressing mutant human APP that models amyloid deposition, it is possible to compare contributions of trisomy 21 and APP/Aβ overexpression to phenotypes in the genotypically different offspring. The work presented in this thesis therefore characterises AD-related phenotypes in progeny of the Tc1xJ20 cross. I first established a primary cortical culture model from early postnatal Tc1xJ20 pups, which would allow the in vitro observation and manipulation of cortical neurons in a more accessible system compared to in vivo study. To assess the validity and utility of these cultures, they were characterized for APP expression, Aβ production, proportion of neuronal cells in culture and levels of mosaicism for the Hsa21 chromosome. These in vitro phenotypes obtained were compared with relevant in vivo observations in Tc1xJ20 mice. Secondly, to study neuroinflammation and glial reactivity, I developed a digital analysis protocol to systematically quantify morphological characteristics of microglia and astrocytes visualized by immunohistochemistry in Tc1xJ20 brain sections. To further identify AD-related phenotypes that may be differentially influenced by genotype, I annotated data obtained from a pilot RNA sequencing study of Tc1xJ20 hippocampal tissues, identified gene candidates of interest, and explored functions that may be altered by genotype by clustering differentially expressed genes by associated functions. These results therefore allow for discussion and evaluation of the novel Tc1xJ20 model for identifying novel genetic contributions of trisomy 21 on AD phenotypes, apart from APP.
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