New technologies in the study of Alzheimer’s disease aetiology
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Date
2025-12-12
Authors
Vaughan, Michael B.
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Publisher
University College Cork
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Abstract
Alzheimer’s disease (AD) is the most prevalent form of dementia, projected to affect over 150 million people worldwide by 2050. Clinically, AD manifests as progressive memory loss and cognitive decline. Neuropathologically, it is characterised by extracellular amyloid-β plaque deposition and intracellular neurofibrillary tau tangle formation, followed by synaptic loss and neural cell death. To date, candidate therapies and interventions have been developed almost exclusively in transgenic animal models, yet little success has been achieved in clinical trials. This translational failing has driven a growing departure from the classical amyloid-cascade hypothesis, upon which these animal models were developed, towards several alternative hypotheses of AD aetiology. Ethical and practical limitations on accessing living human brain tissue for research have, until recently, left the field without an appropriate experimental system to evaluate these alternative hypotheses.
This thesis is primarily concerned with the utility of human induced pluripotent stem cell (iPSC)-based two- and three-dimensional neural culture technologies to investigate these alternative hypotheses of AD in a species-relevant model. Initially, we worked on developing neural progenitor cells (NPCs), mature dentate gyrus (DG) like neurons using a novel differentiation protocol, and cerebral organoids from iPSCs derived from healthy control donors and from a patient carrying the PSEN1M139V mutation. Building on these iPSC-derived materials, we examined two major mechanisms central to alternative hypotheses of AD in NPCs; calcium dysregulation and altered metabolic function. Using live-cell calcium imaging and Seahorse metabolic flux analysis, we characterized how PSEN1M139V NPCs differ from controls in intracellular Ca2+ handling and bioenergetic profiles. Finally, we reviewed current evidence derived from human studies and human cellular or tissue models for herpes simplex virus (HSV)-induced disruption of the neuronal intracellular trafficking system in AD development. Although primary data in human cells are limited, alterations in lysosomal load, endoplasmic reticulum and Golgi architecture, and upregulation of activity-regulated cytoskeleton-associated protein (ARC) mRNA, emerge as promising metrics of disruption for future HSV studies in human iPSC-derived systems.
In summary, this work (1) validates presenilin-mutant neural phenotypes previously observed only in animal models, (2) generated an efficient differentiation method for DG like mature neurons, and (3) synthesised the human-specific evidence linking HSV infection to intraneuronal trafficking disruption.
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Keywords
Alzheimer's disease , iPSC , Organoid , Calcium , HSV
Citation
Vaughan, M. B. 2025. New technologies in the study of Alzheimer’s disease aetiology. PhD Thesis, University College Cork.