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Title: Alzheimer's disease in Down syndrome : mapping modifiers of Alzheimer's pathology in novel mouse crosses
Author: Tosh, Justin
ISNI:       0000 0004 7660 7984
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Down syndrome (DS) occurs due to complete or partial inheritance of an extra copy of Human chromosome 21 (Hsa21) causing abnormal gene dosage and a greatly increased risk of developing Alzheimer's disease (AD). The amyloid precursor protein (APP) gene is found on Hsa21, and inheriting three copies of this gene alone is sufficient to cause early onset familial AD. However, Hsa21 genes other than APP may influence AD-DS phenotypes and pathogenesis. To assay for dosage-sensitive genes that interact with AD phenotypes, I separately crossed two segmentally trisomic mouse models of DS with the 'J20' TgAPP mouse model of APP/Aβ pathology. In this study, I demonstrate that double mutant animals carrying the J20 TgAPP transgene and trisomic for 32 mouse orthologues of genes on Hsa21 (excluding mouse App) between Mis18a and Runx1 exhibit a dramatic increase in sudden death compared to J20 littermates. Additionally these animals display a significant reduction of Aβ42 aggregation in the cortex at 6 and 12 months of age. In a second cross between J20 and the Dp3Tyb mouse model (trisomic for 37 mouse gene Hsa21 orthologues between Mir802 and Zbtb21) resulted in a rescue of the sudden death phenotype in double mutants compared to their J20 littermates and an increase in Aβ42 aggregation in the cortex at 12 months of age. This study maps distinct groups of dosage-sensitive chromosome 21 genes which can modify Alzheimer's disease phenotypes and pathogenesis in the mouse. Further understanding of the causative genes could lead to novel drug targets and therapeutic interventions for AD-DS and people in the general population with AD.
Supervisor: Wiseman, F. ; Fisher, E. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available