Wenz, Katharina; (2025) Investigating candidate genes for amyloid-β accumulation and toxicity in Alzheimer’s disease-Down syndrome. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Down Syndrome (DS), caused by trisomy of chromosome 21 (Hsa21), is the most common genetic cause of early-onset Alzheimer’s disease (termed Alzheimer’s disease-Down Syndrome, AD-DS). Early AD pathology is characterised by extracellular amyloid-b (Ab) deposition generated through sequential cleavage of the Hsa21 encoded amyloid precursor protein (APP). Triplication of APP has been causally implicated in early-onset AD (EOAD). However, pre-clinical studies in mice have demonstrated that an additional copy of Hsa21 genes other than APP is sufficient to increase Ab deposition and exacerbate cognitive decline but which gene(s) mediate this effect has not been elucidated. In this study, I used a Drosophila melanogaster model of amyloid accumulation to assess whether pan-neuronal overexpression of single Hsa21 orthologues can modulate Ab toxicity and accumulation. I screened thirty-five genes and identified seven potential modifiers, though not all findings could be replicated, indicating that overexpression of single Hsa21 orthologues may not be sufficient to modify amyloid pathology. Subsequently, I selected two genes of interest, Usp47 (USP25) and ATPsynCF6 (ATP5J), for further characterisation. To determine whether USP25 and ATP5J could impact Ab pathology in AD-DS, I used human post-mortem brain tissue from individuals with AD-DS, EOAD and healthy ageing controls to assess whether these genes are dosage sensitive in DS. I found a trend towards reduction of USP25 with AD but no difference in ATP5J at the protein level and a significant upregulation of gene expression in neuronal populations. Additionally, differential gene expression analysed from a single-nuclear RNA sequencing (snRNAseq) dataset revealed a signature of dysregulated pathways related to impaired synaptic function and neuronal polarisation in AD-DS. Lastly, combining information from the literature and our snRNAseq dataset, I explored additional Hsa21 candidate modifiers of Ab toxicity/accumulation, highlighting a potential role of TTC3.

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