Chi, Haoyu; (2025) Investigation of metabolic dysfunction associated with Down Syndrome/Alzheimer's Disease linked neurodegeneration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Dementia, most commonly caused by Alzheimer’s Disease, represents a major clinical problem, yet it remains poorly understood, and treatment options remain limited. While the life expectancy of people with Down syndrome (DS or trisomy 21 – T21) has significantly increased over the past decades, they have a very high risk of developing early-onset dementia with clinical and histopathological features closely resembling those of Alzheimer’s disease (known as Down syndrome associated Alzheimer’s Disease – DS-AD). The cause of this dementia is not fully understood, but has been attributed to the triplication of the amyloid precursor protein (APP) gene in T21. I have used patient-derived cell models to explore changes in cellular metabolism associated with DS/AD. These include fibroblasts, iPSC-derived neural progenitor cells (NPCs), and iPSC-derived cortical neurons both with trisomy 21 and with isolated triplication of the APP gene, paired with age-matched fibroblasts or isogenic controls. I have used an array of assays to report mitochondrial metabolic state, amyloid species expression, reactive oxygen species (ROS) production, and calcium signalling homeostasis. In DS fetal skin fibroblasts, mitochondrial membrane potential was reduced, while the expression of APP and mitochondrial calcium uniporter (MCU) were upregulated. In iPSC-derived NPCs, the expression of APP was also elevated, but other metabolic dysfunctions were not recapitulated. Metabolic dysfunction became more evident with differentiation, and the iPSC-derived neurons showed more robust cellular phenotypes, including elevated expression of APP species, reduced mitochondrial respiration and membrane potential, elevated production of ROS, glutathione depletion, and disrupted mitochondrial and ER calcium signalling. Furthermore, iPSC-derived cortical neurons with isolated triplication of APP (from a patient with early onset AD) showed more severe phenotypes than T21 DS neurons. These results show that disease-related metabolic phenotypes are cell type-specific and are closely associated with the dosage of both APP and other genes on chromosome 21.

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