Abstract

Cellular modelling of trisomy 21 as an approach to understand Alzheimer’s disease

Dean Nizetic, Professor Of Molecular Medicine, Nanyang Technological University

Down Syndrome (DS) is the most common genetic cause of intellectual disability and is associated with an increased risk of Alzheimer’s disease (AD). The LonDownS Consortium aims to draw correlations between dementia, cognitive defects, mouse models and genetics with in vitro defects in neurons derived from DS induced pluripotent stem cells (iPSCs). For iPSCs, our two strategies are: (i) isogenic iPSC DS models, (ii) iPSCs from dupAPP and (iii) iPSCs generated from adults and infants, at extremes of the DS spectrum for intensity of pathology. For (i), we developed an integration-free isogenic DS iPSC model by using fibroblasts of an adult with constitutional mosaicism for DS that reproduce several cellular pathologies, including increased ß-amyloid, mitochondrial abnormalities, and an increase in DNA double strand breaks indicating accelerated ageing. 3D cerebral organoids differentiated from isogenic iPSCs were found to recapitulate aspects of human brain structure and layering. As for (ii), iPSCs have been generated from one dupAPP patient, and for (iii), to maximize consent, hair follicles and/or blood samples are collected from participants clinically stratified for cognitive ability and dementia. So far, >400 DS adults have been recruited with >120 keratinocyte lines isolated, with 14 adults considered as extremes. iPSC lines have been established from 8 extremes, 4 with early onset dementia and 4 with late/no diagnosis of dementia. We have also reproduced some of the cellular phenotypes on primary human foetal neurospheres of T21 and gestational age matched normal controls, sampled in the Singaporean population.